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Sample records for complement pathway deregulation

  1. Alternative complement pathway deregulation is correlated with dengue severity.

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    Eduardo J M Nascimento

    Full Text Available BACKGROUND: The complement system, a key component that links the innate and adaptive immune responses, has three pathways: the classical, lectin, and alternative pathways. In the present study, we have analyzed the levels of various complement components in blood samples from dengue fever (DF and dengue hemorrhagic fever (DHF patients and found that the level of complement activation is associated with disease severity. METHODS AND RESULTS: Patients with DHF had lower levels of complement factor 3 (C3; p = 0.002 and increased levels of C3a, C4a and C5a (p<0.0001 when compared to those with the less severe form, DF. There were no significant differences between DF and DHF patients in the levels of C1q, immunocomplexes (CIC-CIq and CRP. However, small but statistically significant differences were detected in the levels of MBL. In contrast, the levels of two regulatory proteins of the alternative pathway varied widely between DF and DHF patients: DHF patients had higher levels of factor D (p = 0.01, which cleaves factor B to yield the active (C3bBb C3 convertase, and lower levels of factor H (p = 0.03, which inactivates the (C3bBb C3 convertase, than did DF patients. When we considered the levels of factors D and H together as an indicator of (C3bBb C3 convertase regulation, we found that the plasma levels of these regulatory proteins in DHF patients favored the formation of the (C3bBb C3 convertase, whereas its formation was inhibited in DF patients (p<0.0001. CONCLUSION: The data suggest that an imbalance in the levels of regulatory factors D and H is associated with an abnormal regulation of complement activity in DHF patients.

  2. Cancer and deregulation of stem cells pathways

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    Filipe Correia Martins

    2011-12-01

    Full Text Available Stem cells may have an important etiological role in cancer. Their classic regulatory pathways are deregulated in tumors, strengthening the stem cell theory of cancer. In this manuscript, we review Wnt, Notch and Hedhehog pathways, describing which of their factors may be responsible for the neoplastic development. Furthermore, we classify these elements as oncogenes or tumor suppressor genes, demonstrating their mutation implications in cancer. The activation of these pathways is associated with the expression of certain genes which maintain proliferation and apoptosis inhibition. Further work should be carried out in the future in order to control tumor development by controlling these signaling cascades.

  3. The lectin pathway of complement

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    Ballegaard, Vibe Cecilie Diederich; Haugaard, Anna Karen; Garred, P

    2014-01-01

    The pattern recognition molecules of the lectin complement pathway are important components of the innate immune system with known functions in host-virus interactions. This paper summarizes current knowledge of how these intriguing molecules, including mannose-binding lectin (MBL), Ficolin-1, -2...

  4. The Lectin Pathway of Complement and Biocompatibility

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    Hein, Estrid; Garred, Peter

    2015-01-01

    In modern health technologies the use of biomaterials in the form of stents, haemodialysis tubes, artificial implants, bypass circuits etc. is rapidly expanding. The exposure of synthetic, foreign surfaces to the blood and tissue of the host, calls for strict biocompatibility in respect to contac...... been broadly documented. However, the specific role of lectin pathway and the pattern recognition molecules initiating the pathway has only been transiently investigated. Here we review the current data on the field....... activation, the coagulation system and the complement system. The complement system is an important part of the initial immune response and consists of fluid phase molecules in the blood stream. Three different activation pathways can initiate the complement system, the lectin, the classical...

  5. Lectin Complement Pathway Proteins in Healthy Individuals

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    Troldborg, Anne; Hansen, Annette; Hansen, Søren W K

    2017-01-01

    Since the discovery of the lectin pathway of complement activation, numerous clinical cohorts have been examined for one or more of the proteins, with the intention of uncovering the functions of the proteins or with the aim of discovering new biomarkers or diagnostic tools. To unveil the abnormal......, it is pivotal to know the normal. Our aim was to describe the concentrations of the eleven known proteins of the lectin pathway in serum and plasma and to uncover possible gender differences, age and diurnal variations, which must be taken into account for investigations in different cohorts. We examined...... the concentrations of all lectin pathway proteins (mannan-binding lectin (MBL), H-ficolin, L-ficolin, M-ficolin, collectin-K1, collectin-L1, MBL-associated serine protease 2 (MASP-2), MASP-3, MBL associated protein of 44 kDa (MAp44) and MAp19 in 300 Danish blood donors in serum and EDTA plasma in established assays...

  6. Complement pathways and meningococcal disease : diagnostic aspects

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    Sjöholm, A G; Truedsson, L; Jensenius, Jens Christian

    2001-01-01

    Complement is an immunological effector system that bridges innate and acquired immunity in several ways. There is a striking association between susceptibility to meningococcal disease and various forms of complement deficiency (1,2). In defense against bacterial infection, the most important...

  7. Novel Evasion Mechanisms of the Classical Complement Pathway.

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    Garcia, Brandon L; Zwarthoff, Seline A; Rooijakkers, Suzan H M; Geisbrecht, Brian V

    2016-09-15

    Complement is a network of soluble and cell surface-associated proteins that gives rise to a self-amplifying, yet tightly regulated system with fundamental roles in immune surveillance and clearance. Complement becomes activated on the surface of nonself cells by one of three initiating mechanisms known as the classical, lectin, and alternative pathways. Evasion of complement function is a hallmark of invasive pathogens and hematophagous organisms. Although many complement-inhibition strategies hinge on hijacking activities of endogenous complement regulatory proteins, an increasing number of uniquely evolved evasion molecules have been discovered over the past decade. In this review, we focus on several recent investigations that revealed mechanistically distinct inhibitors of the classical pathway. Because the classical pathway is an important and specific mediator of various autoimmune and inflammatory disorders, in-depth knowledge of novel evasion mechanisms could direct future development of therapeutic anti-inflammatory molecules.

  8. Lessons learned from mice deficient in lectin complement pathway molecules

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    Genster, Ninette; Takahashi, Minoru; Sekine, Hideharu

    2014-01-01

    in complement activation, pathogen infection, coagulation, host tissue injury and developmental biology have been revealed by in vivo investigations. This review provides an overview of the mice deficient in lectin pathway molecules and highlights some of the most important findings that have resulted from......The lectin pathway of the complement system is initiated when the pattern-recognition molecules, mannose-binding lectin (MBL), ficolins or collectin-11, bind to invading pathogens or damaged host cells. This leads to activation of MBL/ficolin/collectin-11 associated serine proteases (MASPs), which...... in turn activate downstream complement components, ultimately leading to elimination of the pathogen. Mice deficient in the key molecules of lectin pathway of complement have been generated in order to build knowledge of the molecular mechanisms of the lectin pathway in health and disease. Despite...

  9. Non-specific adsorption of complement proteins affects complement activation pathways of gold nanomaterials.

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    Quach, Quang Huy; Kah, James Chen Yong

    2017-04-01

    The complement system is a key humoral component of innate immunity, serving as the first line of defense against intruders, including foreign synthetic nanomaterials. Although gold nanomaterials (AuNMs) are widely used in nanomedicine, their immunological response is not well understood. Using AuNMs of three shapes commonly used in biomedical applications: spherical gold nanoparticles, gold nanostars and gold nanorods, we demonstrated that AuNMs activated whole complement system, leading to the formation of SC5b-9 complex. All three complement pathways were simultaneously activated by all the AuNMs. Recognition molecules of the complement system interacted with all AuNMs in vitro, except for l-ficolin, but the correlation between these interactions and corresponding complement pathway activation was only observed in the classical and alternative pathways. We also observed the mediating role of complement activation in cellular uptake of all AuNMs by human U937 promonocytic cells, which expresses complement receptors. Taken together, our results highlighted the potential immunological challenges for clinical applications of AuNMs that were often overlooked.

  10. Quantitative Modeling of the Alternative Pathway of the Complement System.

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    Zewde, Nehemiah; Gorham, Ronald D; Dorado, Angel; Morikis, Dimitrios

    2016-01-01

    The complement system is an integral part of innate immunity that detects and eliminates invading pathogens through a cascade of reactions. The destructive effects of the complement activation on host cells are inhibited through versatile regulators that are present in plasma and bound to membranes. Impairment in the capacity of these regulators to function in the proper manner results in autoimmune diseases. To better understand the delicate balance between complement activation and regulation, we have developed a comprehensive quantitative model of the alternative pathway. Our model incorporates a system of ordinary differential equations that describes the dynamics of the four steps of the alternative pathway under physiological conditions: (i) initiation (fluid phase), (ii) amplification (surfaces), (iii) termination (pathogen), and (iv) regulation (host cell and fluid phase). We have examined complement activation and regulation on different surfaces, using the cellular dimensions of a characteristic bacterium (E. coli) and host cell (human erythrocyte). In addition, we have incorporated neutrophil-secreted properdin into the model highlighting the cross talk of neutrophils with the alternative pathway in coordinating innate immunity. Our study yields a series of time-dependent response data for all alternative pathway proteins, fragments, and complexes. We demonstrate the robustness of alternative pathway on the surface of pathogens in which complement components were able to saturate the entire region in about 54 minutes, while occupying less than one percent on host cells at the same time period. Our model reveals that tight regulation of complement starts in fluid phase in which propagation of the alternative pathway was inhibited through the dismantlement of fluid phase convertases. Our model also depicts the intricate role that properdin released from neutrophils plays in initiating and propagating the alternative pathway during bacterial infection.

  11. Complement-Mediated Glomerular Diseases: A Tale of 3 Pathways

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    Andrew S. Bomback

    2016-09-01

    Full Text Available A renewed interest in the role of complement in the pathogenesis of glomerular diseases has improved our understanding of their basic, underlying physiology. All 3 complement pathways—classical, lectin, and alternative—have been implicated in glomerular lesions both rare (e.g., dense deposit disease and common (e.g., IgA nephropathy. Here we review the basic function of these pathways and highlight, with a disease-specific focus, how activation can lead to glomerular injury. We end by exploring the promise of complement-targeted therapies as disease-specific interventions for glomerular diseases.

  12. The proteomic signature of NPM/ALK reveals deregulation of multiple cellular pathways.

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    Lim, Megan S; Carlson, Mary L; Crockett, David K; Fillmore, G Chris; Abbott, David R; Elenitoba-Johnson, Olaotan F; Tripp, Sheryl R; Rassidakis, George Z; Medeiros, L Jeffrey; Szankasi, Philippe; Elenitoba-Johnson, Kojo S J

    2009-08-20

    Constitutive expression of the chimeric NPM/ALK fusion protein encoded by the t(2;5)(p32;q35) is a key oncogenic event in the pathogenesis of most anaplastic large cell lymphomas (ALCLs). The proteomic network alterations produced by this aberration remain largely uncharacterized. Using a mass spectrometry (MS)-driven approach to identify changes in protein expression caused by the NPM/ALK fusion, we identified diverse NPM/ALK-induced changes affecting cell proliferation, ribosome synthesis, survival, apoptosis evasion, angiogenesis, and cytoarchitectural organization. MS-based findings were confirmed using Western blotting and/or immunostaining of NPM/ALK-transfected cells and ALK-deregulated lymphomas. A subset of the proteins distinguished NPM/ALK-positive ALCLs from NPM/ALK-negative ALCLs and Hodgkin lymphoma. The multiple NPM/ALK-deregulated pathways identified by MS analysis also predicted novel biologic effects of NPM/ALK expression. In this regard, we showed loss of cell adhesion as a consequence of NPM/ALK expression in a kinase-dependent manner, and sensitivity of NPM/ALK-positive ALCLs to inhibition of the RAS, p42/44ERK, and FRAP/mTOR signaling pathways. These findings reveal that the NPM/ALK alteration affects diverse cellular pathways, and provide novel insights into NPM/ALK-positive ALCL pathobiology. Our studies carry important implications for the use of MS-driven approaches for the elucidation of neoplastic pathobiology, the identification of novel diagnostic biomarkers, and pathogenetically relevant therapeutic targets.

  13. The Lectin Pathway of Complement and Rheumatic Heart Disease

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    Marcia Holsbach Beltrame

    2015-01-01

    Full Text Available The innate immune system is the first line of host defense against infection and is comprised of humoral and cellular mechanisms that recognize potential pathogens within minutes or hours of entry. The effector components of innate immunity include epithelial barriers, phagocytes and natural killer cells, as well as cytokines and the complement system. Complement plays an important role in the immediate response against microorganisms, including Streptococcus sp. The lectin pathway is one of three pathways by which the complement system can be activated. This pathway is initiated by the binding of mannose-binding lectin (MBL, collectin K-1 (CL-K1 and ficolins (Ficolin-1, Ficolin-2 and Ficolin-3 to microbial surface oligosaccharides and acetylated residues, respectively. Upon binding to target molecules, MBL, CL-K1 and ficolins form complexes with MBL-associated serine proteases 1 and 2 (MASP-1 and MASP-2, which cleave C4 and C2 forming the C3 convertase (C4b2a. Subsequent activation of complement cascade leads to opsonization, phagocytosis and lysis of target microorganisms through the formation of the membrane attack complex. In addition, activation of complement may induce several inflammatory effects, such as expression of adhesion molecules, chemotaxis and activation of leukocytes, release of reactive oxygen species and secretion of cytokines and chemokines. In this chapter, we review the general aspects of the structure, function and genetic polymorphism of lectin pathway components and discuss most recent understanding on the role of the lectin pathway in the predisposition and clinical progression of Rheumatic Fever (RF.

  14. Aluminum hydroxide adjuvant differentially activates the three complement pathways with major involvement of the alternative pathway.

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    Güven, Esin; Duus, Karen; Laursen, Inga; Højrup, Peter; Houen, Gunnar

    2013-01-01

    Al(OH)3 is the most common adjuvant in human vaccines, but its mode of action remains poorly understood. Complement involvement in the adjuvant properties of Al(OH)3 has been suggested in several reports together with a depot effect. It is here confirmed that Al(OH)3 treatment of serum depletes complement components and activates the complement system. We show that complement activation by Al(OH)3 involves the three major pathways by monitoring complement components in Al(OH)3-treated serum and in Al(OH)3-containing precipitates. Al(OH)3 activation of complement results in deposition of C3 cleavage products and membrane attack complex (MAC) and in generation of the anaphylatoxins C3a and C5a. Complement activation was time dependent and inhibited by chelation with EDTA but not EGTA+Mg(2+). We thus confirm that Al(OH)3 activates the complement system and show that the alternative pathway is of major importance.

  15. Aluminum hydroxide adjuvant differentially activates the three complement pathways with major involvement of the alternative pathway.

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    Esin Güven

    Full Text Available Al(OH3 is the most common adjuvant in human vaccines, but its mode of action remains poorly understood. Complement involvement in the adjuvant properties of Al(OH3 has been suggested in several reports together with a depot effect. It is here confirmed that Al(OH3 treatment of serum depletes complement components and activates the complement system. We show that complement activation by Al(OH3 involves the three major pathways by monitoring complement components in Al(OH3-treated serum and in Al(OH3-containing precipitates. Al(OH3 activation of complement results in deposition of C3 cleavage products and membrane attack complex (MAC and in generation of the anaphylatoxins C3a and C5a. Complement activation was time dependent and inhibited by chelation with EDTA but not EGTA+Mg(2+. We thus confirm that Al(OH3 activates the complement system and show that the alternative pathway is of major importance.

  16. Aluminum Hydroxide Adjuvant Differentially Activates the Three Complement Pathways with Major Involvement of the Alternative Pathway

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    Güven, Esin; Duus, Karen; Laursen, Inga; Højrup, Peter; Houen, Gunnar

    2013-01-01

    Al(OH)3 is the most common adjuvant in human vaccines, but its mode of action remains poorly understood. Complement involvement in the adjuvant properties of Al(OH)3 has been suggested in several reports together with a depot effect. It is here confirmed that Al(OH)3 treatment of serum depletes complement components and activates the complement system. We show that complement activation by Al(OH)3 involves the three major pathways by monitoring complement components in Al(OH)3-treated serum and in Al(OH)3-containing precipitates. Al(OH)3 activation of complement results in deposition of C3 cleavage products and membrane attack complex (MAC) and in generation of the anaphylatoxins C3a and C5a. Complement activation was time dependent and inhibited by chelation with EDTA but not EGTA+Mg2+. We thus confirm that Al(OH)3 activates the complement system and show that the alternative pathway is of major importance. PMID:24040248

  17. Structural Basis for the Function of Complement Component C4 within the Classical and Lectin Pathways of Complement

    DEFF Research Database (Denmark)

    Mortensen, Sofia; Kidmose, Rune Thomas; Petersen, Steen Vang;

    2015-01-01

    Complement component C4 is a central protein in the classical and lectin pathways within the complement system. During activation of complement, its major fragment C4b becomes covalently attached to the surface of pathogens and altered self-tissue, where it acts as an opsonin marking the surface...... for removal. Moreover, C4b provides a platform for assembly of the proteolytically active convertases that mediate downstream complement activation by cleavage of C3 and C5. In this article, we present the crystal and solution structures of the 195-kDa C4b. Our results provide the molecular details...

  18. Deregulation of Listeria monocytogenes virulence gene expression by two distinct and semi-independent pathways.

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    Milenbachs Lukowiak, Andrea; Mueller, Kimberly J; Freitag, Nancy E; Youngman, Philip

    2004-02-01

    Expression of the major virulence cluster in Listeria monocytogenes is positively regulated by the transcription factor PrfA and is influenced by several environmental factors, including the presence of readily metabolized carbohydrates such as cellobiose and glucose. Although little is understood about the mechanisms through which environmental factors influence expression of the PrfA regulon, evidence for structural and functional similarities of PrfA to the CRP-FNR family of regulatory proteins suggests the possibility that PrfA activity could be modulated by a small molecule ligand. The identity of components of the PrfA-associated regulatory pathway was sought through the isolation of mutants that exhibit high levels of PrfA-controlled gene expression in the presence of cellobiose or glucose. Here are described the properties and preliminary genetic analysis in two different genetic loci, gcr and csr, both unlinked by general transduction to the major virulence cluster. A mutation in gcr deregulates the expression of PrfA-controlled genes in the presence of several repressing sugars and other environmental conditions, a phenotype similar to that of a G145S substitution in PrfA itself. A mutation in the csr locus, within csrA, results in a cellobiose-specific defect in virulence gene regulation. Gene products encoded by the csr locus share homology with proteins involved in the sensing and transport of beta-glucosides in other bacteria. Mutations in both gcr and csr are required for full relief of cellobiose-mediated repression of the PrfA regulon. These results suggest the existence of two semi-independent pathways for cellobiose-mediated repression and further reconcile conflicting reports in previous literature concerning the repressive effects of carbohydrates on virulence gene expression in L. monocytogenes.

  19. Complement alternative pathway activation in human nonalcoholic steatohepatitis.

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    Filip M Segers

    Full Text Available The innate immune system plays a major role in the pathogenesis of nonalcoholic steatohepatitis (NASH. Recently we reported complement activation in human NASH. However, it remained unclear whether the alternative pathway of complement, which amplifies C3 activation and which is frequently associated with pathological complement activation leading to disease, was involved. Here, alternative pathway components were investigated in liver biopsies of obese subjects with healthy livers (n = 10 or with NASH (n = 12 using quantitative PCR, Western blotting, and immunofluorescence staining. Properdin accumulated in areas where neutrophils surrounded steatotic hepatocytes, and colocalized with the C3 activation product C3c. C3 activation status as expressed by the C3c/native C3 ratio was 2.6-fold higher (p<0.01 in subjects with NASH despite reduced native C3 concentrations (0.94±0.12 vs. 0.57±0.09; p<0.01. Hepatic properdin levels positively correlated with levels of C3c (rs = 0.69; p<0.05 and C3c/C3 activation ratio (rs = 0.59; p<0.05. C3c, C3 activation status (C3c/C3 ratio and properdin levels increased with higher lobular inflammation scores as determined according to the Kleiner classification (C3c: p<0.01, C3c/C3 ratio: p<0.05, properdin: p<0.05. Hepatic mRNA expression of factor B and factor D did not differ between subjects with healthy livers and subjects with NASH (factor B: 1.00±0.19 vs. 0.71±0.07, p = 0.26; factor D: 1.00±0.21 vs. 0.66±0.14, p = 0.29;. Hepatic mRNA and protein levels of Decay Accelerating Factor tended to be increased in subjects with NASH (mRNA: 1.00±0.14 vs. 2.37±0.72; p = 0.22; protein: 0.51±0.11 vs. 1.97±0.67; p = 0.28. In contrast, factor H mRNA was downregulated in patients with NASH (1.00±0.09 vs. 0.71±0.06; p<0.05 and a similar trend was observed with hepatic protein levels (1.12±0.16 vs. 0.78±0.07; p = 0.08. Collectively, these data suggest a role for alternative

  20. AMD and the alternative complement pathway: genetics and functional implications.

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    Tan, Perciliz L; Bowes Rickman, Catherine; Katsanis, Nicholas

    2016-06-21

    Age-related macular degeneration (AMD) is an ocular neurodegenerative disorder and is the leading cause of legal blindness in Western societies, with a prevalence of up to 8 % over the age of 60, which continues to increase with age. AMD is characterized by the progressive breakdown of the macula (the central region of the retina), resulting in the loss of central vision including visual acuity. While its molecular etiology remains unclear, advances in genetics and genomics have illuminated the genetic architecture of the disease and have generated attractive pathomechanistic hypotheses. Here, we review the genetic architecture of AMD, considering the contribution of both common and rare alleles to susceptibility, and we explore the possible mechanistic links between photoreceptor degeneration and the alternative complement pathway, a cascade that has emerged as the most potent genetic driver of this disorder.

  1. Structural Basis for the Function of Complement Component C4 within the Classical and Lectin Pathways of Complement

    DEFF Research Database (Denmark)

    Mortensen, Sofia; Kidmose, Rune Thomas; Petersen, Steen Vang;

    2015-01-01

    Complement component C4 is a central protein in the classical and lectin pathways within the complement system. During activation of complement, its major fragment C4b becomes covalently attached to the surface of pathogens and altered self-tissue, where it acts as an opsonin marking the surface...... for removal. Moreover, C4b provides a platform for assembly of the proteolytically active convertases that mediate downstream complement activation by cleavage of C3 and C5. In this article, we present the crystal and solution structures of the 195-kDa C4b. Our results provide the molecular details...... of substrate recognition. We propose an overall molecular model for the classical pathway C5 convertase in complex with C5, suggesting that C3b increases the affinity for the substrate by inducing conformational changes in C4b rather than a direct interaction with C5. C4b-specific features revealed by our...

  2. Collectin-11/MASP complex formation triggers activation of the lectin complement pathway--the fifth lectin pathway initiation complex

    DEFF Research Database (Denmark)

    Ma, Ying Jie; Skjoedt, Mikkel-Ole; Garred, Peter

    2013-01-01

    complement pathway regulator MAP-1. Furthermore, we found that complex formation between recombinant collectin-11 and recombinant MASP-2 on Candida albicans leads to deposition of C4b. Native collectin-11 in serum mediated complement activation and deposition of C4b and C3b, and formation of the terminal...... complement complex on C. albicans. Moreover, spiking collectin-11-depleted serum, which did not mediate complement activation, with recombinant collectin-11 restored the complement activation capability. These results define collectin-11 as the fifth recognition molecule in the lectin complement pathway...

  3. Genetic control of the alternative pathway of complement in humans and age-related macular degeneration.

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    Hecker, Laura A; Edwards, Albert O; Ryu, Euijung; Tosakulwong, Nirubol; Baratz, Keith H; Brown, William L; Charbel Issa, Peter; Scholl, Hendrik P; Pollok-Kopp, Beatrix; Schmid-Kubista, Katharina E; Bailey, Kent R; Oppermann, Martin

    2010-01-01

    Activation of the alternative pathway of complement is implicated in common neurodegenerative diseases including age-related macular degeneration (AMD). We explored the impact of common variation in genes encoding proteins of the alternative pathway on complement activation in human blood and in AMD. Genetic variation across the genes encoding complement factor H (CFH), factor B (CFB) and component 3 (C3) was determined. The influence of common haplotypes defining transcriptional and translational units on complement activation in blood was determined in a quantitative genomic association study. Individual haplotypes in CFH and CFB were associated with distinct and novel effects on plasma levels of precursors, regulators and activation products of the alternative pathway of complement in human blood. Further, genetic variation in CFH thought to influence cell surface regulation of complement did not alter plasma complement levels in human blood. Plasma markers of chronic activation (split-products Ba and C3d) and an activating enzyme (factor D) were elevated in AMD subjects. Most of the elevation in AMD was accounted for by the genetic variation controlling complement activation in human blood. Activation of the alternative pathway of complement in blood is under genetic control and increases with age. The genetic variation associated with increased activation of complement in human blood also increased the risk of AMD. Our data are consistent with a disease model in which genetic variation in the complement system increases the risk of AMD by a combination of systemic complement activation and abnormal regulation of complement activation in local tissues.

  4. Molecular interplay between bacteria and the terminal complement pathway

    NARCIS (Netherlands)

    Berends, E.T.M.

    2015-01-01

    The plasma proteins of the complement system fulfill important immune defense functions, including opsonization of bacteria for phagocytosis, generation of chemo-attractants and direct bacterial killing via assembly of the Membrane Attack Complex (MAC or C5b-9 complex). The terminal complement pathw

  5. Molecular interplay between bacteria and the terminal complement pathway

    NARCIS (Netherlands)

    Berends, E.T.M.

    2015-01-01

    The plasma proteins of the complement system fulfill important immune defense functions, including opsonization of bacteria for phagocytosis, generation of chemo-attractants and direct bacterial killing via assembly of the Membrane Attack Complex (MAC or C5b-9 complex). The terminal complement

  6. De-regulation of gene expression and alternative splicing affects distinct cellular pathways in the aging hippocampus

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    Roman M Stilling

    2014-11-01

    Full Text Available Aging is accompanied by gradually increasing impairment of cognitive abilities and constitutes the main risk factor of neurodegenerative conditions like Alzheimer’s disease. The underlying mechanisms are however not well understood. Here we analyze the hippocampal transcriptome of young adult mice and two groups of mice at advanced age using RNA sequencing. This approach enabled us to test differential expression of coding and non-coding transcripts, as well as differential splicing and RNA editing. We report a specific age-associated gene expression signature that is associated with major genetic risk factors for late-onset Alzheimer’s disease. This signature is dominated by neuroinflammatory processes, specifically activation of the complement system at the level of increased gene expression, while de-regulation of neuronal plasticity appears to be mediated by compromised RNA splicing.

  7. Metabolic Disorder, Inflammation, and Deregulated Molecular Pathways Converging in Pancreatic Cancer Development: Implications for New Therapeutic Strategies

    Energy Technology Data Exchange (ETDEWEB)

    Motoo, Yoshiharu, E-mail: motoo@kanazawa-med.ac.jp [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Shimasaki, Takeo [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Division of Translational & Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa (Japan); Ishigaki, Yasuhito [Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Nakajima, Hideo [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Kawakami, Kazuyuki; Minamoto, Toshinari [Division of Translational & Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa (Japan)

    2011-01-24

    Pancreatic cancer develops and progresses through complex, cumulative biological processes involving metabolic disorder, local inflammation, and deregulated molecular pathways. The resulting tumor aggressiveness hampers surgical intervention and renders pancreatic cancer resistant to standard chemotherapy and radiation therapy. Based on these pathologic properties, several therapeutic strategies are being developed to reverse refractory pancreatic cancer. Here, we outline molecular targeting therapies, which are primarily directed against growth factor receptor-type tyrosine kinases deregulated in tumors, but have failed to improve the survival of pancreatic cancer patients. Glycogen synthase kinase-3β (GSK3β) is a member of a serine/threonine protein kinase family that plays a critical role in various cellular pathways. GSK3β has also emerged as a mediator of pathological states, including glucose intolerance, inflammation, and various cancers (e.g., pancreatic cancer). We review recent studies that demonstrate the anti-tumor effects of GSK3β inhibition alone or in combination with chemotherapy and radiation. GSK3β inhibition may exert indirect anti-tumor actions in pancreatic cancer by modulating metabolic disorder and inflammation.

  8. Metabolic Disorder, Inflammation, and Deregulated Molecular Pathways Converging in Pancreatic Cancer Development: Implications for New Therapeutic Strategies

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    Toshinari Minamoto

    2011-01-01

    Full Text Available Pancreatic cancer develops and progresses through complex, cumulative biological processes involving metabolic disorder, local inflammation, and deregulated molecular pathways. The resulting tumor aggressiveness hampers surgical intervention and renders pancreatic cancer resistant to standard chemotherapy and radiation therapy. Based on these pathologic properties, several therapeutic strategies are being developed to reverse refractory pancreatic cancer. Here, we outline molecular targeting therapies, which are primarily directed against growth factor receptor-type tyrosine kinases deregulated in tumors, but have failed to improve the survival of pancreatic cancer patients. Glycogen synthase kinase-3β (GSK3β is a member of a serine/threonine protein kinase family that plays a critical role in various cellular pathways. GSK3β has also emerged as a mediator of pathological states, including glucose intolerance, inflammation, and various cancers (e.g., pancreatic cancer. We review recent studies that demonstrate the anti-tumor effects of GSK3β inhibition alone or in combination with chemotherapy and radiation. GSK3β inhibition may exert indirect anti-tumor actions in pancreatic cancer by modulating metabolic disorder and inflammation.

  9. SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis

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    Ferreira, Viviana P.; Fazito Vale, Vladimir; Pangburn, Michael K.; Abdeladhim, Maha; Ferreira Mendes-Sousa, Antonio; Coutinho-Abreu, Iliano V.; Rasouli, Manoochehr; Brandt, Elizabeth A.; Meneses, Claudio; Lima, Kolyvan Ferreira; Nascimento Araújo, Ricardo; Horácio Pereira, Marcos; Kotsyfakis, Michalis; Oliveira, Fabiano; Kamhawi, Shaden; Ribeiro, Jose M. C.; Gontijo, Nelder F.; Collin, Nicolas; Valenzuela, Jesus G.

    2016-01-01

    Blood-feeding insects inject potent salivary components including complement inhibitors into their host’s skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti-complement activity has the same chromatographic properties as the Lu. longipalpis salivary gland homogenate (SGH)counterparts and anti-rSALO antibodies blocked the classical pathway complement activity of rSALO and SGH. Both rSALO and SGH inhibited C4b deposition and cleavage of C4. rSALO, however, did not inhibit the protease activity of C1s nor the enzymatic activity of factor Xa, uPA, thrombin, kallikrein, trypsin and plasmin. Importantly, rSALO did not inhibit the alternative or the lectin pathway of complement. In conclusion our data shows that SALO is a specific classical pathway complement inhibitor present in the saliva of Lu. longipalpis. Importantly, due to its small size and specificity, SALO may offer a therapeutic alternative for complement classical pathway-mediated pathogenic effects in human diseases. PMID:26758086

  10. Blockade of Alternative Complement Pathway in Dense Deposit Disease

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    Aurore Berthe-Aucejo

    2014-01-01

    Full Text Available A patient aged 17 with dense deposit disease associated with complement activation, circulating C3 Nef, and Factor H mutation presented with nephrotic syndrome and hypertension. Steroid therapy, plasma exchange, and rituximab failed to improve proteinuria and hypertension despite a normalization of the circulating sC5b9 complex. Eculizumab, a monoclonal antibody directed against C5, was used to block the terminal product of the complement cascade. The dose was adapted to achieve a CH50 below 10%, but proteinuria and blood pressure were not improved after 3 months of treatment.

  11. Blockade of Alternative Complement Pathway in Dense Deposit Disease

    Science.gov (United States)

    Sacquépée, Mathieu; Fila, Marc; Peuchmaur, Michel; Perrier-Cornet, Emilia; Frémeaux-Bacchi, Véronique; Deschênes, Georges

    2014-01-01

    A patient aged 17 with dense deposit disease associated with complement activation, circulating C3 Nef, and Factor H mutation presented with nephrotic syndrome and hypertension. Steroid therapy, plasma exchange, and rituximab failed to improve proteinuria and hypertension despite a normalization of the circulating sC5b9 complex. Eculizumab, a monoclonal antibody directed against C5, was used to block the terminal product of the complement cascade. The dose was adapted to achieve a CH50 below 10%, but proteinuria and blood pressure were not improved after 3 months of treatment. PMID:24672732

  12. Oversulfated chondroitin sulfate inhibits the complement classical pathway by potentiating C1 inhibitor.

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    Zhao-Hua Zhou

    Full Text Available Oversulfated chondroitin sulfate (OSCS has become the subject of multidisciplinary investigation as a non-traditional contaminant in the heparin therapeutic preparations that were linked to severe adverse events. In this study, it was found that OSCS inhibited complement fixation on bacteria and bacterial lysis mediated by the complement classical pathway. The inhibition of complement by OSCS is not due to interference with antibody/antigen interaction or due to consumption of C3 associated with FXII-dependent contact system activation. However, OSCS complement inhibition is dependent on C1 inhibitor (C1inh since the depletion of C1inh from either normal or FXII-deficient complement plasma prevents OSCS inhibition of complement activity. Surface plasmon resonance measurements revealed that immobilized C1inhibitor bound greater than 5-fold more C1s in the presence of OSCS than in presence of heparin. Although heparin can also inhibit complement, OSCS and OSCS contaminated heparin are more potent inhibitors of complement. Furthermore, polysulfated glycosaminoglycan (PSGAG, an anti-inflammatory veterinary medicine with a similar structure to OSCS, also inhibited complement in the plasma of dogs and farm animals. This study provides a new insight that in addition to the FXII-dependent activation of contact system, oversulfated and polysulfated chondroitin-sulfate can inhibit complement activity by potentiating the classical complement pathway regulator C1inh. This effect on C1inh may play a role in inhibiting inflammation as well as impacting bacterial clearance.

  13. Altered metabolic pathways in clear cell renal cell carcinoma: A meta-analysis and validation study focused on the deregulated genes and their associated networks.

    Science.gov (United States)

    Zaravinos, Apostolos; Pieri, Myrtani; Mourmouras, Nikos; Anastasiadou, Natassa; Zouvani, Ioanna; Delakas, Dimitris; Deltas, Constantinos

    2014-01-01

    Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cell carcinoma (RCC). It is one of the most therapy-resistant carcinomas, responding very poorly or not at all to radiotherapy, hormonal therapy and chemotherapy. A more comprehensive understanding of the deregulated pathways in ccRCC can lead to the development of new therapies and prognostic markers. We performed a meta- analysis of 5 publicly available gene expression datasets and identified a list of co- deregulated genes, for which we performed extensive bioinformatic analysis coupled with experimental validation on the mRNA level. Gene ontology enrichment showed that many proteins are involved in response to hypoxia/oxygen levels and positive regulation of the VEGFR signaling pathway. KEGG analysis revealed that metabolic pathways are mostly altered in ccRCC. Similarly, Ingenuity Pathway Analysis showed that the antigen presentation, inositol metabolism, pentose phosphate, glycolysis/gluconeogenesis and fructose/mannose metabolism pathways are altered in the disease. Cellular growth, proliferation and carbohydrate metabolism, were among the top molecular and cellular functions of the co-deregulated genes. qRT-PCR validated the deregulated expression of several genes in Caki-2 and ACHN cell lines and in a cohort of ccRCC tissues. NNMT and NR3C1 increased expression was evident in ccRCC biopsies from patients using immunohistochemistry. ROC curves evaluated the diagnostic performance of the top deregulated genes in each dataset. We show that metabolic pathways are mostly deregulated in ccRCC and we highlight those being most responsible in its formation. We suggest that these genes are candidate predictive markers of the disease.

  14. Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice

    OpenAIRE

    Britschgi Markus; Takeda-Uchimura Yoshiko; Rockenstein Edward; Johns Hudson; Masliah Eliezer; Wyss-Coray Tony

    2012-01-01

    Abstract Background The neuronal microtubule-associated protein tau becomes hyperphosphorylated and forms aggregates in tauopathies but the processes leading to this pathological hallmark are not understood. Because tauopathies are accompanied by neuroinflammation and the complement cascade forms a key innate immune pathway, we asked whether the complement system has a role in the development of tau pathology. Finding...

  15. Solution Structures of Complement C2 and its C4 Complexes Propose Pathway Specific Mechanisms for Control and Activation of the Complement Proconvertases

    DEFF Research Database (Denmark)

    Mortensen, Sofia; Jensen, Jan Kristian; Andersen, Gregers Rom

    2016-01-01

    The lectin (LP) and classical (CP) pathways are two of the three main activation cascades of the complement system. These pathways start with recognition of different pathogen- or danger-associated molecular patterns and include identical steps of proteolytic activation of complement component C4...

  16. An assay for the mannan-binding lectin pathway of complement activation

    DEFF Research Database (Denmark)

    Petersen, Steen Vang; Thiel, S; Jensen, L;

    2001-01-01

    The mannan-binding lectin (MBL) pathway of complement activation has been established as the third pathway of complement activation. MBL is a carbohydrate-binding serum protein, which circulates in complex with serine proteases known as mannan-binding lectin associated serine proteases (MASPs...... activation. Therefore, in a generally applicable complement activation assay specific for the MBL pathway, the activity of the classical pathway must be inhibited. This can be accomplished by exploiting the finding that high ionic strength buffers inhibit the binding of C1q to immune complexes and disrupt...... the C1 complex, whereas the carbohydrate-binding activity of MBL and the integrity of the MBL complex is maintained under hypertonic conditions. In the assay described here, the specific C4b-depositing capacity of the MBL pathway was determined by incubating serum diluted in buffer containing 1 M Na...

  17. Tissue microarray methodology identifies complement pathway activation and dysregulation in progressive multiple sclerosis.

    Science.gov (United States)

    Loveless, Sam; Neal, James W; Howell, Owain W; Harding, Katharine E; Sarkies, Patrick; Evans, Rhian; Bevan, Ryan J; Hakobyan, Svetlana; Harris, Claire L; Robertson, Neil P; Morgan, Bryan Paul

    2017-07-14

    The complement pathway has potential contributions to both white (WM) and grey matter (GM) pathology in Multiple Sclerosis (MS). A quantitative assessment of complement involvement is lacking. Here we describe the use of Tissue MicroArray (TMA) methodology in conjunction with immunohistochemistry to investigate the localization of complement pathway proteins in progressive MS cortical GM and subcortical WM. Antibodies targeting complement proteins C1q, C3b, regulatory proteins C1 inhibitor (C1INH, complement receptor 1 (CR1), clusterin, factor H (FH) and the C5a anaphylatoxin receptor (C5aR) were utilised alongside standard markers of tissue pathology. All stained slides were digitised for quantitative analysis. We found that numbers of cells immunolabelled for HLA-DR, GFAP, C5aR, C1q and C3b were increased in WM lesions (WML) and GM lesions (GML) compared to normal appearing WM (NAWM) and GM (NAGM), respectively. The complement regulators C1INH, CR1, FH and clusterin were more abundant in WM lesions, while the number of C1q+ neurons were increased and the number of C1INH+, clusterin+, FH+ and CR1+ neurons decreased in GM lesions. The number of complement component positive cells (C1q, C3b) correlated with complement regulator expression in WM, but there was no statistical association between complement activation and regulator expression in the GM. We conclude that TMA methodology and quantitative analysis provides evidence of complement dysregulation in MS GML, including an association of the numerical density of C1q+ cells with tissue lesions. Our work confirms that complement activation and dysregulation occur in all cases of progressive MS and suggest that complement may provide potential biomarkers of the disease. © 2017 International Society of Neuropathology.

  18. Evasion Mechanisms Used by Pathogens to Escape the Lectin Complement Pathway

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    Anne Rosbjerg

    2017-05-01

    Full Text Available The complement system is a crucial defensive network that protects the host against invading pathogens. It is part of the innate immune system and can be initiated via three pathways: the lectin, classical and alternative activation pathway. Overall the network compiles a group of recognition molecules that bind specific patterns on microbial surfaces, a group of associated proteases that initiates the complement cascade, and a group of proteins that interact in proteolytic complexes or the terminal pore-forming complex. In addition, various regulatory proteins are important for controlling the level of activity. The result is a pro-inflammatory response meant to combat foreign microbes. Microbial elimination is, however, not a straight forward procedure; pathogens have adapted to their environment by evolving a collection of evasion mechanisms that circumvent the human complement system. Complement evasion strategies features different ways of exploiting human complement proteins and moreover features different pathogen-derived proteins that interfere with the normal processes. Accumulated, these mechanisms target all three complement activation pathways as well as the final common part of the cascade. This review will cover the currently known lectin pathway evasion mechanisms and give examples of pathogens that operate these to increase their chance of invasion, survival and dissemination.

  19. Age-related macular degeneration: Complement in action.

    Science.gov (United States)

    van Lookeren Campagne, Menno; Strauss, Erich C; Yaspan, Brian L

    2016-06-01

    The complement system plays a key role in host-defense against common pathogens but must be tightly controlled to avoid inflammation and tissue damage. Polymorphisms in genes encoding two important negative regulators of the alternative complement pathway, complement factor H (CFH) and complement factor I (CFI), are associated with the risk for Age-Related Macular Degeneration (AMD), a leading cause of vision impairment in the ageing population. In this review, we will discuss the genetic basis of AMD and the potential impact of complement de-regulation on disease pathogenesis. Finally, we will highlight recent therapeutic approaches aimed at controlling complement activation in patients with AMD.

  20. Alternative complement pathway deficiency ameliorates chronic smoke-induced functional and morphological ocular injury.

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    Alex Woodell

    Full Text Available BACKGROUND: Age-related macular degeneration (AMD, a complex disease involving genetic variants and environmental insults, is among the leading causes of blindness in Western populations. Genetic and histologic evidence implicate the complement system in AMD pathogenesis; and smoking is the major environmental risk factor associated with increased disease risk. Although previous studies have demonstrated that cigarette smoke exposure (CE causes retinal pigment epithelium (RPE defects in mice, and smoking leads to complement activation in patients, it is unknown whether complement activation is causative in the development of CE pathology; and if so, which complement pathway is required. METHODS: Mice were exposed to cigarette smoke or clean, filtered air for 6 months. The effects of CE were analyzed in wildtype (WT mice or mice without a functional complement alternative pathway (AP; CFB(-/- using molecular, histological, electrophysiological, and behavioral outcomes. RESULTS: CE in WT mice exhibited a significant reduction in function of both rods and cones as determined by electroretinography and contrast sensitivity measurements, concomitant with a thinning of the nuclear layers as measured by SD-OCT imaging and histology. Gene expression analyses suggested that alterations in both photoreceptors and RPE/choroid might contribute to the observed loss of function, and visualization of complement C3d deposition implies the RPE/Bruch's membrane (BrM complex as the target of AP activity. RPE/BrM alterations include an increase in mitochondrial size concomitant with an apical shift in mitochondrial distribution within the RPE and a thickening of BrM. CFB(-/- mice were protected from developing these CE-mediated alterations. CONCLUSIONS: Taken together, these findings provide clear evidence that ocular pathology generated in CE mice is dependent on complement activation and requires the AP. Identifying animal models with RPE/BrM damage and verifying

  1. Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice

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    Britschgi Markus

    2012-09-01

    Full Text Available Abstract Background The neuronal microtubule-associated protein tau becomes hyperphosphorylated and forms aggregates in tauopathies but the processes leading to this pathological hallmark are not understood. Because tauopathies are accompanied by neuroinflammation and the complement cascade forms a key innate immune pathway, we asked whether the complement system has a role in the development of tau pathology. Findings We tested this hypothesis in two mouse models, which expressed either a central inhibitor of complement or lacked an inhibitor of the terminal complement pathway. Complement receptor-related gene/protein y is the natural inhibitor of the central complement component C3 in rodents. Expressing a soluble variant (sCrry reduced the number of phospho-tau (AT8 epitope positive neurons in the brain stem, cerebellum, cortex, and hippocampus of aged P301L mutant tau/sCrry double-transgenic mice compared with tau single-transgenic littermates (JNPL3 line. CD59a is the major inhibitor of formation of the membrane attack complex in mice. Intrahippocampal injection of adeno-associated virus encoding mutant human P301L tau into Cd59a−/− mice resulted in increased numbers of AT8-positive cells compared with wild-type controls. This was accompanied by neuronal and synaptic loss and reduced dendritic integrity. Conclusions Our data in two independent mouse models with genetic changes in key regulators of the complement system support the hypothesis that the terminal pathway has an active role in the development of tau pathology. We propose that inhibition of the terminal pathway may be beneficial in tauopathies.

  2. The Emerging Role of Complement Lectin Pathway in Trypanosomatids: Molecular Bases in Activation, Genetic Deficiencies, Susceptibility to Infection, and Complement System-Based Therapeutics

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    Ingrid Evans-Osses

    2013-01-01

    Full Text Available The innate immune system is evolutionary and ancient and is the pivotal line of the host defense system to protect against invading pathogens and abnormal self-derived components. Cellular and molecular components are involved in recognition and effector mechanisms for a successful innate immune response. The complement lectin pathway (CLP was discovered in 1990. These new components at the complement world are very efficient. Mannan-binding lectin (MBL and ficolin not only recognize many molecular patterns of pathogens rapidly to activate complement but also display several strategies to evade innate immunity. Many studies have shown a relation between the deficit of complement factors and susceptibility to infection. The recently discovered CLP was shown to be important in host defense against protozoan microbes. Although the recognition of pathogen-associated molecular patterns by MBL and Ficolins reveal efficient complement activations, an increase in deficiency of complement factors and diversity of parasite strategies of immune evasion demonstrate the unsuccessful effort to control the infection. In the present paper, we will discuss basic aspects of complement activation, the structure of the lectin pathway components, genetic deficiency of complement factors, and new therapeutic opportunities to target the complement system to control infection.

  3. MINI-REVIEW: SYSTEMIC LUPUS ERYTHEMATOSUS AND DEFICIENCIES OF EARLY COMPONENTS OF THE COMPLEMENT CLASSICAL PATHWAY

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    Lourdes eIsaac

    2016-02-01

    Full Text Available The complement system plays an important role in the innate and acquired immune response against pathogens. It consists of more than 30 proteins found in soluble form or attached to cell membranes. Most complement proteins circulate in inactive forms and can be sequentially activated by the Classical, Alternative or Lectin Pathways. Biological functions such as opsonization, removal of apoptotic cells, adjuvant function, activation of B lymphocytes, degranulation of mast cells and basophils, solubilization and clearance of immune complex and cell lysis are dependent on complement activation. Although the activation of the complement system is important to avoid infections, it also can contribute to the inflammatory response triggered by immune complex deposition in tissues in auto-immune diseases. Paradoxically, the deficiency of early complement proteins from the Classical Pathway is strongly associated with development of systemic lupus erythematous (SLE - mainly C1q deficiency (93% and C4 deficiency (75%. The aim of this review is to focus on the deficiencies of early components of the Classical Pathway (C1q, C1r, C1s, C4, C2 proteins in SLE patients.

  4. Increased activity of the mannan-binding lectin complement activation pathway in patients with colorectal cancer

    DEFF Research Database (Denmark)

    Ytting, H; Jensenius, J C; Christensen, Ib Jarle

    2004-01-01

    BACKGROUND: Postoperative bacterial infectious complications are frequent in patients with colorectal cancer (CRC), with subsequent increased recurrence rates and poor prognosis. Deficiency of the mannan-binding lectin (MBL) complement activation pathway may cause increased risk of infection...... with colorectal cancer compared with healthy persons. However, similar frequencies of MBL pathway deficiency are observed in patients and healthy persons....... in certain patient groups. It is hypothesized that a deficient MBL pathway might be more frequent among patients with CRC than in healthy individuals. The MBL pathway was therefore evaluated in serum obtained preoperatively from 193 patients with primary CRC and in serum from 150 healthy volunteers. METHODS...

  5. Classical Complement Pathway Activation in the Kidneys of Women With Preeclampsia.

    Science.gov (United States)

    Penning, Marlies; Chua, Jamie S; van Kooten, Cees; Zandbergen, Malu; Buurma, Aletta; Schutte, Joke; Bruijn, Jan Anthonie; Khankin, Eliyahu V; Bloemenkamp, Kitty; Karumanchi, S Ananth; Baelde, Hans

    2015-07-01

    A growing body of evidence suggests that complement dysregulation plays a role in the pathogenesis of preeclampsia. The kidney is one of the major organs affected in preeclampsia. Because the kidney is highly susceptible to complement activation, we hypothesized that preeclampsia is associated with renal complement activation. We performed a nationwide search for renal autopsy material in the Netherlands using a computerized database (PALGA). Renal tissue was obtained from 11 women with preeclampsia, 25 pregnant controls, and 14 nonpregnant controls with hypertension. The samples were immunostained for C4d, C1q, mannose-binding lectin, properdin, C3d, C5b-9, IgA, IgG, and IgM. Preeclampsia was significantly associated with renal C4d-a stable marker of complement activation-and the classical pathway marker C1q. In addition, the prevalence of IgM was significantly higher in the kidneys of the preeclamptic women. No other complement markers studied differed between the groups. Our findings in human samples were validated using a soluble fms-like tyrosine kinase 1 mouse model of preeclampsia. The kidneys in the soluble fms-like tyrosine kinase 1-injected mice had significantly more C4 deposits than the control mice. The association between preeclampsia and renal C4d, C1q, and IgM levels suggests that the classical complement pathway is involved in the renal injury in preeclampsia. Moreover, our finding that soluble fms-like tyrosine kinase 1-injected mice develop excess C4 deposits indicates that angiogenic dysregulation may play a role in complement activation within the kidney. We suggest that inhibiting complement activation may be beneficial for preventing the renal manifestations of preeclampsia. © 2015 American Heart Association, Inc.

  6. A metalloproteinase mirolysin of Tannerella forsythia inhibits all pathways of the complement system

    Science.gov (United States)

    Jusko, Monika; Potempa, Jan; Mizgalska, Danuta; Bielecka, Ewa; Ksiazek, Miroslaw; Riesbeck, Kristian; Garred, Peter; Eick, Sigrun; Blom, Anna M.

    2015-01-01

    Recent reports focusing on virulence factors of periodontal pathogens implicated proteinases as major determinants of remarkable pathogenicity of these species, with special emphasis on their capacity to modulate complement activity. In particular, bacteria-mediated cleavage of C5 and subsequent release of C5a seems to be an important phenomenon in the manipulation of the local inflammatory response in periodontitis. Here we present mirolysin, a novel metalloproteinase secreted by Tannerella forsythia, a well-recognized pathogen strongly associated with periodontitis. Mirolysin exhibited a strong effect on all complement pathways. It inhibited the classical and lectin complement pathways due to efficient degradation of mannose-binding lectin, ficolin-2, ficolin-3 and C4, while inhibition of the alternative pathway was caused by degradation of C5. This specificity toward complement largely resembled the activity of a previously characterized metalloproteinase of T. forsythia, karilysin. Interestingly, mirolysin released the biologically active C5a peptide in human plasma and induced migration of neutrophils. Importantly, we demonstrated that combination of mirolysin with karilysin, as well as a cysteine proteinase of another periodontal pathogen, Prevotella intermedia, resulted in a strong synergistic effect on complement. Furthermore, mutant strains of T. forsythia, devoid of either mirolysin or karilysin, showed diminished survival in human serum, providing further evidence for the synergistic inactivation of complement by these metalloproteinases. Taken together, our findings on interactions of mirolysin with complement significantly add to the understanding of immune evasion strategies of T. forsythia, and expand the knowledge on molecular mechanisms driving pathogenic events in the infected periodontium. PMID:26209620

  7. A Metalloproteinase Mirolysin of Tannerella forsythia Inhibits All Pathways of the Complement System.

    Science.gov (United States)

    Jusko, Monika; Potempa, Jan; Mizgalska, Danuta; Bielecka, Ewa; Ksiazek, Miroslaw; Riesbeck, Kristian; Garred, Peter; Eick, Sigrun; Blom, Anna M

    2015-09-01

    Recent reports focusing on virulence factors of periodontal pathogens implicated proteinases as major determinants of remarkable pathogenicity of these species, with special emphasis on their capacity to modulate complement activity. In particular, bacteria-mediated cleavage of C5 and subsequent release of C5a seems to be an important phenomenon in the manipulation of the local inflammatory response in periodontitis. In this study, we present mirolysin, a novel metalloproteinase secreted by Tannerella forsythia, a well-recognized pathogen strongly associated with periodontitis. Mirolysin exhibited a strong effect on all complement pathways. It inhibited the classical and lectin complement pathways due to efficient degradation of mannose-binding lectin, ficolin-2, ficolin-3, and C4, whereas inhibition of the alternative pathway was caused by degradation of C5. This specificity toward complement largely resembled the activity of a previously characterized metalloproteinase of T. forsythia, karilysin. Interestingly, mirolysin released the biologically active C5a peptide in human plasma and induced migration of neutrophils. Importantly, we demonstrated that combination of mirolysin with karilysin, as well as a cysteine proteinase of another periodontal pathogen, Prevotella intermedia, resulted in a strong synergistic effect on complement. Furthermore, mutant strains of T. forsythia, devoid of either mirolysin or karilysin, showed diminished survival in human serum, providing further evidence for the synergistic inactivation of complement by these metalloproteinases. Taken together, our findings on interactions of mirolysin with complement significantly add to the understanding of immune evasion strategies of T. forsythia and expand the knowledge on molecular mechanisms driving pathogenic events in the infected periodontium.

  8. Ficolin-3-mediated lectin complement pathway activation in patients with subarachnoid hemorrhage

    DEFF Research Database (Denmark)

    Zanier, Elisa R; Zangari, Rosalia; Munthe-Fog, Lea

    2014-01-01

    OBJECTIVES: To assess the involvement of ficolin-3, the main initiator of the lectin complement pathway (LCP), in subarachnoid hemorrhage (SAH) pathology and outcome. METHODS: In this preliminary exploratory study, plasma concentration of ficolin-3 and of ficolin-3-mediated functional LCP activit...

  9. Depressed activation of the lectin pathway of complement in hereditary angioedema

    DEFF Research Database (Denmark)

    Varga, L; Széplaki, G; Laki, J

    2008-01-01

    ) in three complement activation pathways. Functional activity of the CP, LP and AP were measured in the sera of 68 adult patients with hereditary angioedema (HAE) and 64 healthy controls. In addition, the level of C1q, MBL, MBL-associated serine protease-2 (MASP-2), C4-, C3- and C1INH was measured...

  10. Toward a structure-based comprehension of the lectin pathway of complement

    DEFF Research Database (Denmark)

    Kjaer, Troels R; Thiel, Steffen; Andersen, Gregers R

    2013-01-01

    To initiate the lectin pathway of complement pattern recognition molecules bind to surface-linked carbohydrates or acetyl groups on pathogens or damaged self-tissue. This leads to activation of the serine proteases MASP-1 and MASP-2 resulting in deposition of C4 on the activator and assembly...

  11. Study of the optimal reaction conditions for assay of the mouse alternative complement pathway

    NARCIS (Netherlands)

    Dijk, H. van; Rademaker, P.M.; Klerx, J.P.A.M.; Willers, J.M.M.

    1985-01-01

    The optimal reaction conditions for hemolytic assay of alternative complement pathway activity in mouse serum were investigated. A microtiter system was used, in which a number of 7.5×106 rabbit erythrocytes per test well appeared to be optimal. Rabbit erythrocytes were superior as target cells over

  12. Determination of alternative pathway of complement activity in mouse serum using rabbit erythrocytes

    NARCIS (Netherlands)

    Dijk, H. van; Rademaker, P.M.; Willers, J.M.N

    1980-01-01

    Rabbit, mouse and sheep erythrocytes expressing different concentrations of membrane sialic acid were used to study possible modes of activation of the alternative complement (C) pathway in mouse, human and guinea pig serum. Mouse erythrocytes activated only human serum, whereas rabbit erythrocytes

  13. Spontaneous deregulation

    NARCIS (Netherlands)

    Edelman, Benjamin; Geradin, Damien

    2016-01-01

    Platform businesses such as Airbnb and Uber have risen to success partly by sidestepping laws and regulations that encumber their traditional competitors. Such rule flouting is what the authors call “spontaneous private deregulation,” and it’s happening in a growing number of industries. The authors

  14. Spontaneous deregulation

    NARCIS (Netherlands)

    Edelman, Benjamin; Geradin, Damien

    2016-01-01

    Platform businesses such as Airbnb and Uber have risen to success partly by sidestepping laws and regulations that encumber their traditional competitors. Such rule flouting is what the authors call “spontaneous private deregulation,” and it’s happening in a growing number of industries. The authors

  15. Spontaneous deregulation

    NARCIS (Netherlands)

    Edelman, Benjamin; Geradin, Damien

    Platform businesses such as Airbnb and Uber have risen to success partly by sidestepping laws and regulations that encumber their traditional competitors. Such rule flouting is what the authors call “spontaneous private deregulation,” and it’s happening in a growing number of industries. The authors

  16. Human L-ficolin, a recognition molecule of the lectin activation pathway of complement, activates complement by binding to pneumolysin, the major toxin of Streptococcus pneumoniae.

    Science.gov (United States)

    Ali, Youssif M; Kenawy, Hany I; Muhammad, Adnan; Sim, Robert B; Andrew, Peter W; Schwaeble, Wilhelm J

    2013-01-01

    The complement system is an essential component of the immune response, providing a critical line of defense against different pathogens including S. pneumoniae. Complement is activated via three distinct pathways: the classical (CP), the alternative (AP) and the lectin pathway (LP). The role of Pneumolysin (PLY), a bacterial toxin released by S. pneumoniae, in triggering complement activation has been studied in vitro. Our results demonstrate that in both human and mouse sera complement was activated via the CP, initiated by direct binding of even non-specific IgM and IgG3 to PLY. Absence of CP activity in C1q(-/-) mouse serum completely abolished any C3 deposition. However, C1q depleted human serum strongly opsonized PLY through abundant deposition of C3 activation products, indicating that the LP may have a vital role in activating the human complement system on PLY. We identified that human L-ficolin is the critical LP recognition molecule that drives LP activation on PLY, while all of the murine LP recognition components fail to bind and activate complement on PLY. This work elucidates the detailed interactions between PLY and complement and shows for the first time a specific role of the LP in PLY-mediated complement activation in human serum.

  17. Marked reduction of AKT1 expression and deregulation of AKT1-associated pathways in peripheral blood mononuclear cells of schizophrenia patients.

    Directory of Open Access Journals (Sweden)

    Nico J M van Beveren

    Full Text Available BACKGROUND: Recent studies have suggested that deregulated AKT1 signaling is associated with schizophrenia. We hypothesized that if this is indeed the case, we should observe both decreased AKT1 expression as well as deregulation of AKT1 regulated pathways in Peripheral Blood Mononuclear Cells (PBMCs of schizophrenia patients. OBJECTIVES: To examine PBMC expression levels of AKT1 in schizophrenia patients versus controls, and to examine whether functional biological processes in which AKT1 plays an important role are deregulated in schizophrenia patients. METHODS/RESULTS: A case-control study, investigating whole-genome PBMC gene expression in male, recent onset (<5 years schizophrenia patients (N = 41 as compared to controls (N = 29. Genes, differentially expressed between patients and controls were identified using ANOVA with Benjamini-Hochberg correction (false discovery rate (FDR = 0.05. Functional aspects of the deregulated set of genes were investigated with the Ingenuity Pathway Analysis (IPA Software Tool. We found significantly decreased PBMC expression of AKT1 (p<0.001, t = -4.25 in the patients. AKT1 expression was decreased in antipsychotic-free or -naive patients (N = 11, in florid psychotic (N = 20 and in remitted (N = 21 patients. A total of 1224 genes were differentially expressed between patients and controls (FDR = 0.05. Functional analysis of the entire deregulated gene set indicated deregulated canonical pathways involved in a large number of cellular processes: immune system, cell adhesion and neuronal guidance, neurotrophins and (neural growth factors, oxidative stress and glucose metabolism, and apoptosis and cell-cycle regulation. Many of these processes are associated with AKT1. CONCLUSIONS: We show significantly decreased PBMC gene expression of AKT1 in male, recent-onset schizophrenia patients. Our observations suggest that decreased PBMC AKT1 expression is a stable trait in recent onset

  18. Functional characterization of the lectin pathway of complement in human serum.

    Science.gov (United States)

    Roos, Anja; Bouwman, Lee H; Munoz, Jeric; Zuiverloon, Tahlita; Faber-Krol, Maria C; Fallaux-van den Houten, Francien C; Klar-Mohamad, Ngaisah; Hack, C Erik; Tilanus, Marcel G; Daha, Mohamed R

    2003-01-01

    Mannan-binding lectin (MBL) is a major initiator of the lectin pathway (LP) of complement. Polymorphisms in exon 1 of the MBL gene are associated with impaired MBL function and infections. Functional assays to assess the activity of the classical pathway (CP) and the alternative pathway (AP) of complement in serum are broadly used in patient diagnostics. We have now developed a functional LP assay that enables the specific quantification of autologous MBL-dependent complement activation in human serum. Complement activation was assessed by ELISA using coated mannan to assess the LP and coated IgM to assess the CP. Normal human serum (NHS) contains IgG, IgA and IgM antibodies against mannan, as shown by ELISA. These antibodies are likely to induce CP activation. Using C1q-blocking and MBL-blocking mAb, it was confirmed that both the LP and the CP contribute to complement activation by mannan. In order to quantify LP activity without interference of the CP, LP activity was measured in serum in the presence of C1q-blocking Ab. Activation of serum on coated IgM via the CP resulted in a dose-dependent deposition of C1q, C4, C3, and C5b-9. This activation and subsequent complement deposition was completely inhibited by the C1q-blocking mAb 2204 and by polyclonal Fab anti-C1q Ab. Evaluation of the LP in the presence of mAb 2204 showed a strong dose-dependent deposition of C4, C3, and C5b-9 using serum from MBL-wildtype (AA) but not MBL-mutant donors (AB or BB genotype), indicating that complement activation under these conditions is MBL-dependent and C1q-independent. Donors with different MBL genotypes were identified using a newly developed oligonucleotide ligation assay (OLA) for detection of MBL exon 1 polymorphisms. We describe a novel functional assay that enables quantification of autologous complement activation via the LP in full human serum up to the formation of the membrane attack complex. This assay offers novel possibilities for patient diagnostics as well as

  19. Activated complement classical pathway in a murine model of oxygen-induced retinopathy

    Institute of Scientific and Technical Information of China (English)

    Xue-Ying; Tao; Shi-Jie; Zheng; Bo; Lei

    2015-01-01

    AIM: To investigate whether the complement system is involved in a murine model of oxygen-induced retinopathy(OIR).METHODS: Forty C57BL/6J newborn mice were divided randomly into OIR group and control group. OIR was induced by exposing mice to 75% ±2% oxygen from postnatal 7d(P7) to P12 and then recovered in room air.For the control group, the litters were raised in room air.At the postnatal 17d(P17), gene expressions of the complement components of the classical pathway(CP),the mannose-binding lectin(MBL) pathway and the alternative pathway(AP) in the retina were determined by quantitative real-time polymerase chain reaction(RT-PCR). Retinal protein expressions of the key components in the CP were examined by Western blotting.· RESULTS: Whole mounted retina in the OIR mice showed area of central hypoperfusion in both superficial and deep layers and neovascular tufts in the periphery.The expressions of C1 qb and C4 b genes in the OIR retina were significantly higher than those of the controls. The expression of retinal complement factor B(CFB) gene in OIR mice was significantly lower than those of the controls. However, the expressions of C3 and complement factor H(CFH) genes were higher. The protein synthesis of the key components involved in the CP(C1q, C4 and C3) were also significantly higher in OIR mouse retina. Although MBL-associated serine protease 1(MASP1) and MASP2 were detected in both the OIR and the control groups, the expressions were weak and the difference between the two groups was not significant.CONCLUSION: Our data suggest that the complement system CP is activated during the pathogenesis of murine model of OIR.

  20. Demonstration of alternative and classical complement pathway activity in colostrum from buffalo (Bubalus bubalis).

    Science.gov (United States)

    Matheswaran, K; Dhinakar Raj, G; Nachimuthu, K

    2003-09-01

    Buffalo colostrum caused lysis of unsensitized red blood cells (RBC) from sheep, goats, rabbits and chickens. RBC from cattle and buffalo were resistant to lysis. That lysis was due to the presence of natural antibodies to these RBC was ruled out since there was no reduction in haemolytic titres even after adsorption with the respective RBC. The addition of EGTA to the diluent had no effect on the haemolytic activity. These findings indicate the presence of alternative complement pathway (ACP) activity in buffalo colostrum. The haemolytic activity of buffalo complement for unsensitized rabbit RBC was reduced to very low levels by heating at 50 degrees C for 45 min. Treatment with zymosan also inhibited the haemolytic activity, while inulin had no effect. The maximum activity of ACP occurred in the presence of 4 mmol/L Mg(2+) in the diluent. The range of ACP activities in colostrum from buffaloes varied from 4.06 to 8.48 CH50 units/ml. Using a standard system for titrating the classical complement pathway and rabbit red blood cells sensitized with goat haemolysin, the range of complement activity in buffalo colostrum was 4.81-6.77 CH50/ml.

  1. The alternative complement pathway is dysregulated in patients with chronic heart failure

    Science.gov (United States)

    Shahini, Negar; Michelsen, Annika E.; Nilsson, Per H.; Ekholt, Karin; Gullestad, Lars; Broch, Kaspar; Dahl, Christen P.; Aukrust, Pål; Ueland, Thor; Mollnes, Tom Eirik; Yndestad, Arne; Louwe, Mieke C.

    2017-01-01

    The complement system, an important arm of the innate immune system, is activated in heart failure (HF). We hypothesized that HF patients are characterized by an imbalance of alternative amplification loop components; including properdin and complement factor D and the alternative pathway inhibitor factor H. These components and the activation product, terminal complement complex (TCC), were measured in plasma from 188 HF patients and 67 age- and sex- matched healthy controls by enzyme immunoassay. Our main findings were: (i) Compared to controls, patients with HF had significantly increased levels of factor D and TCC, and decreased levels of properdin, particularly patients with advanced clinical disorder (i.e., NYHA functional class IV), (ii) Levels of factor D and properdin in HF patients were correlated with measures of systemic inflammation (i.e., C-reactive protein), neurohormonal deterioration (i.e., Nt-proBNP), cardiac function, and deteriorated diastolic function, (iii) Low levels of factor H and properdin were associated with adverse outcome in univariate analysis and for factor H, this was also seen in an adjusted model. Our results indicate that dysregulation of circulating components of the alternative pathway explain the increased degree of complement activation and is related to disease severity in HF patients. PMID:28195242

  2. Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Kimura Yuko

    2011-01-01

    Full Text Available Abstract Background Complement proteins and activation products have been found associated with neuropathology in Alzheimer's disease (AD. Recently, a C5a receptor antagonist was shown to suppress neuropathology in two murine models of AD, Tg2576 and 3xTg. Previously, a genetic deficiency of C1q in the Tg2576 mouse model showed an accumulation of fibrillar plaques similar to the complement sufficient Tg2576, but reactive glia were significantly decreased and neuronal integrity was improved suggesting detrimental consequences for complement activation in AD. The goal of this study was to define the role of the classical complement activation pathway in the progression of pathology in the 3xTg mouse that develops tangles in addition to fibrillar plaques (more closely reflecting human AD pathology and to assess the influence of complement in a model of AD with a higher level of complement hemolytic activity. Methods 3xTg mice deficient in C1q (3xTgQ-/- were generated, and both 3xTg and 3xTgQ-/- were backcrossed to the BUB mouse strain which has higher in vitro hemolytic complement activity. Mice were aged and perfused, and brain sections stained for pathological markers or analyzed for proinflammatory marker expression. Results 3xTgQ-/- mice showed similar amounts of fibrillar amyloid, reactive glia and hyperphosphorylated tau as the C1q-sufficient 3xTg at the ages analyzed. However, 3xTg and 3xTgQ-/- on the BUB background developed pathology earlier than on the original 3xTg background, although the presence of C1q had no effect on neuropathological and pro-inflammatory markers. In contrast to that seen in other transgenic models of AD, C1q, C4 and C3 immunoreactivity was undetectable on the plaques of 3xTg in any background, although C3 was associated with reactive astrocytes surrounding the plaques. Importantly, properdin a component of the alternative complement pathway was associated with plaques in all models. Conclusions In contrast to

  3. Increased activity of the mannan-binding lectin complement activation pathway in patients with colorectal cancer

    DEFF Research Database (Denmark)

    Ytting, H; Jensenius, Jens Christian; Christensen, I J

    2004-01-01

    in the colon or rectum, and disease stages according to Dukes' classification. No statistical difference (P=0.20) in frequency of MBL deficiency was found between the patients (20%) and the donors (27%). CONCLUSIONS: Overall, the MBL complement activation pathway is significantly increased in patients......BACKGROUND: Postoperative bacterial infectious complications are frequent in patients with colorectal cancer (CRC), with subsequent increased recurrence rates and poor prognosis. Deficiency of the mannan-binding lectin (MBL) complement activation pathway may cause increased risk of infection......: Serum MBL concentrations and MBL/MASP activity were determined using immunofluorometric assays. The levels are presented as the median, inter-quartile range and range. RESULTS: Serum MBL levels were significantly (P

  4. Aluminum hydroxide adjuvant differentially activates the three complement pathways with major involvement of the alternative pathway

    DEFF Research Database (Denmark)

    Güven, Esin; Duus, Karen; Laursen, Inga

    2013-01-01

    Al(OH)3 is the most common adjuvant in human vaccines, but its mode of action remains poorly understood. Complement involvement in the adjuvant properties of Al(OH)3 has been suggested in several reports together with a depot effect. It is here confirmed that Al(OH)3 treatment of serum depletes c...

  5. Properdin and Factor H: Opposing players on the alternative complement pathway see-saw

    Directory of Open Access Journals (Sweden)

    Lubna eKouser

    2013-04-01

    Full Text Available Properdin and factor H are two key regulatory proteins having opposite functions in the alternative complement pathway. Properdin up-regulates the alternative pathway by stabilising the C3bBb complex, whereas factor H down-regulates the pathway by promoting proteolytic degradation of C3b. While factor H is mainly produced in the liver, there are several extrahepatic sources. In addition to the liver, factor H is also synthesized in fetal tubuli, keratinocytes, skin fibroblasts, ocular tissue, adipose tissue, brain, lungs, heart, spleen, pancreas, kidney, muscle, and placenta. Neutrophils are the major source of properdin, and it is also produced by monocytes, T cells and bone marrow progenitor cell line. Properdin is released by neutrophils from intracellular stores following stimulation by N-formyl-methionine-leucine-phenylalanine and tumour necrosis factor alpha. The HEP G2 cells derived from human liver has been found to produce functional properdin. Endothelial cells also produce properdin when induced by shear stress, thus is a physiological source for plasma properdin.. The diverse range of extrahepatic sites for synthesis of these two complement regulators suggests the importance and need for local availability of the proteins. Here, we discuss the significance of the local synthesis of properdin and factor H. This assumes greater importance in view of recently identified unexpected and novel roles of properdin and factor H that are potentially independent of their involvement in the complement regulation.

  6. A zebrafish model for uremic toxicity: role of the complement pathway.

    Science.gov (United States)

    Berman, Nathaniel; Lectura, Melisa; Thurman, Joshua M; Reinecke, James; Raff, Amanda C; Melamed, Michal L; Quan, Zhe; Evans, Todd; Meyer, Timothy W; Hostetter, Thomas H

    2013-01-01

    Many organic solutes accumulate in end-stage renal disease (ESRD) and some are poorly removed with urea-based prescriptions for hemodialysis. However, their toxicities have been difficult to assess. We have employed an animal model, the zebrafish embryo, to test the toxicity of uremic serum compared to control. Serum was obtained from stable ESRD patients predialysis or from normal subjects. Zebrafish embryos 24 h postfertilization were exposed to experimental media at a water:human serum ratio of 3:1. Those exposed to serum from uremic subjects had significantly reduced survival at 8 h (19 ± 18 vs. 94 ± 6%, p 50 kDa, respectively). Heating serum abrogated its toxicity. EDTA, a potent inhibitor of complement by virtue of calcium chelation, reduced the toxicity of uremic serum compared to untreated uremic serum (96 ± 5 vs. 28 ± 20% survival, p < 0.016, chelated vs. nonchelated serum, respectively). Anti-factor B, a specific inhibitor of the alternative complement pathway, reduced the toxicity of uremic serum, compared to untreated uremic serum (98 ± 6 vs. 3 ± 9% survival, p < 0.016, anti-factor B treated vs. nontreated, respectively). Uremic serum is thus more toxic to zebrafish embryos than normal serum. Furthermore, this toxicity is associated with a fraction of large size, is inactivated by heat, and is reduced by both specific and nonspecific inhibitors of complement activation. Together these data lend support to the hypothesis that at least some uremic toxicities may be mediated by complement.

  7. Alternative complement pathway activation during invasive coronary procedures in acute myocardial infarction and stable angina pectoris.

    Science.gov (United States)

    Horváth, Zsófia; Csuka, Dorottya; Vargova, Katarina; Kovács, Andrea; Leé, Sarolta; Varga, Lilian; Préda, István; Tóth Zsámboki, Emese; Prohászka, Zoltán; Kiss, Róbert Gábor

    2016-12-01

    The effect of invasive percutaneous coronary procedures on complement activation has not been elucidated. We enrolled stable angina patients with elective percutaneous coronary intervention (SA-PCI, n=24), diagnostic coronary angiography (CA, n=52) and 23 patients with ST segment elevation myocardial infarction and primary PCI (STEMI-PCI). Complement activation products (C1rC1sC1inh, C3bBbP and SC5b-9) were measured on admission, 6 and 24h after coronary procedures. The alternative pathway product, C3bBbP significantly and reversibly increased 6h after elective PCI (baseline: 7.81AU/ml, 6h: 16.09AU/ml, 24h: 4.27AU/ml, p<0.01, n=23) and diagnostic angiography (baseline: 6.13AU/ml, 6h: 12.08AU/ml, 24h: 5.4AU/ml, p<0.01, n=52). Six hour C3bBbP values correlated with post-procedural CK, creatinine level and the applied contrast material volume (r=0.41, r=0.4, r=0.3, p<0.05, respectively). In STEMI-PCI, baseline C3bBbP level was higher, compared to SA-PCI or CA patients (11.33AU/ml vs. 7.81AU/ml or 6.13AU/ml, p<0.001). Similarly, the terminal complex (SC5b-9) level was already elevated at baseline compared to SA-PCI group (3.49AU/ml vs. 1.87AU/ml, p=0.011). Complement pathway products did not increase further after primary PCI. Elective coronary procedures induced transient alternative complement pathway activation, influenced by the applied contrast volume. In STEMI, the alternative complement pathway is promptly activated during the atherothrombotic event and PCI itself had no further detectable effect.

  8. Significance of complement components C1q and C4 bound to circulating immune complexes in juvenile idiopathic arthritis: support for classical complement pathway activation.

    Science.gov (United States)

    Gilliam, Brooke E; Reed, Melinda R; Chauhan, Anil K; Dehlendorf, Amanda B; Moore, Terry L

    2011-01-01

    Immune complexes (ICs) from sera of juvenile idiopathic arthritis (JIA) patients show increased complement opsonisation; however, a definitive role for involvement of the classical or alternative pathway is not entirely clear. To delineate the role of these pathways, we measured activated complement products bound to circulating IC (CICs) in the sera of JIA patients. Sera from 100 JIA patients and 22 healthy children were collected. C1q, C4, C3, C3d, and membrane attack complex (MAC) bound to CICs were measured by enzyme-linked immunosorbent assay. Data was compared to IgM rheumatoid factor (RF), IgG anti-cyclic citrullinated peptide (CCP) antibodies, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) levels. Mean levels of C1q, C4, and MAC bound to CICs were significantly elevated in JIA patients compared to healthy children. C1q correlated significantly with C4 and MAC bound to CICs and C4 and MAC also demonstrated significant correlation. No significant differences were noted in complement components bound to CICs when evaluating IgM RF, anti-CCP antibody, and CRP positivity. A significant correlation was noted between MAC bound to CICs and ESR. C1q and MAC bound to CICs mean levels were significantly higher in patients with an elevated ESR compared to those with a normal ESR level. JIA patients have elevated levels of complement components bound to CICs, particularly from the classical pathway. Moreover, classical pathway components were associated with ESR, a marker of disease activity. MAC bound to CICs also correlated significantly with ESR, further supporting the notion of complement-mediated tissue injury that is triggered by IC-mediated classical pathway activation.

  9. The lectin pathway of complement activation is a critical component of the innate immune response to pneumococcal infection

    DEFF Research Database (Denmark)

    Ali, Youssif M; Lynch, Nicholas J; Haleem, Kashif S;

    2012-01-01

    to pneumococcal infection and fail to opsonize Streptococcus pneumoniae in the none-immune host. This defect in complement opsonisation severely compromises pathogen clearance in the lectin pathway deficient host. Using sera from mice and humans with defined complement deficiencies, we demonstrate that mouse...

  10. Salivary agglutinin is the major component in human saliva that modulates the lectin pathway of the complement system

    NARCIS (Netherlands)

    Gunput, S.T.G.; Wouters, D.; Nazmi, K.; Cukkemane, N.; Brouwer, M.; Veerman, E.C.I.; Ligtenberg, A.J.M.

    2016-01-01

    Saliva interacts with blood after mucosal damage or leakage of gingival crevicular fluid. Surface-adsorbed salivary agglutinin (SAG) activates the lectin pathway (LP) of the complement system via mannose-binding lectin, while SAG in solution inhibits complement activation. In the present study we

  11. TFPI inhibits lectin pathway of complement activation by direct interaction with MASP-2.

    Science.gov (United States)

    Keizer, Mischa P; Pouw, Richard B; Kamp, Angela M; Patiwael, Sanne; Marsman, Gerben; Hart, Margreet H; Zeerleder, Sacha; Kuijpers, Taco W; Wouters, Diana

    2015-02-01

    The lectin pathway (LP) of complement has a protective function against invading pathogens. Recent studies have also shown that the LP plays an important role in ischemia/reperfusion (I/R)-injury. MBL-associated serine protease (MASP)-2 appears to be crucial in this process. The serpin C1-inhibitor is the major inhibitor of MASP-2. In addition, aprotinin, a Kunitz-type inhibitor, was shown to inhibit MASP-2 activity in vitro. In this study we investigated whether the Kunitz-type inhibitor tissue factor pathway inhibitor (TFPI) is also able to inhibit MASP-2. Ex vivo LP was induced and detected by C4-deposition on mannan-coated plates. The MASP-2 activity was measured in a fluid-phase chromogenic assay. rTFPI in the absence or presence of specific monoclonal antibodies was used to investigate which TFPI-domains contribute to MASP-2 inhibition. Here, we identify TFPI as a novel selective inhibitor of MASP-2, without affecting MASP-1 or the classical pathway proteases C1s and C1r. Kunitz-2 domain of TFPI is required for the inhibition of MASP-2. Considering the role of MASP-2 in complement-mediated I/R-injury, the inhibition of this protease by TFPI could be an interesting therapeutic approach to limit the tissue damage in conditions such as cerebral stroke, myocardial infarction or solid organ transplantation.

  12. A journey through the lectin pathway of complement-MBL and beyond

    DEFF Research Database (Denmark)

    Garred, Peter; Genster, Ninette; Pilely, Katrine;

    2016-01-01

    . They bind to conserved pathogen-specific structures and altered self-antigens and form complexes with the pentraxins to modulate innate immune functions. All molecules exhibit distinct expression in different tissue compartments, but all are found to a varying degree in the circulation. A common feature......, and Carnevale) embryonic development syndrome originates from rare mutations affecting either collectin-11 or MASP-3, indicating a broader functionality of the complement system than previously anticipated. This review summarizes the characteristics of the molecules in the lectin pathway....

  13. Mutations of complement lectin pathway genes MBL2 and MASP2 associated with placental malaria

    Directory of Open Access Journals (Sweden)

    Holmberg Ville

    2012-03-01

    Full Text Available Abstract Background Innate immunity plays a crucial role in the host defense against malaria including Plasmodium falciparum malaria in pregnancy, but the roles of the various underlying genes and mechanisms predisposing to the disease are poorly understood. Methods 98 single-nucletoide polymorphisms were genotyped in a set of 17 functionally related genes of the complement system in 145 primiparous Ghanaian women with placental malaria, defined by placental parasitaemia or malaria pigment, and as a control, in 124 non-affected primiparae. Results Placental malaria was significantly associated with SNPs in the lectin pathway genes MBL2, MASP2, FCN2 and in properdin. In particular, the main African mannose-binding lectin deficiency variant (MBL2*G57E, rs1800451 increased the odds of placental malaria (OR 1.6; permuted p-value 0.014. In contrast, a common MASP2 mutation (R439H, rs12085877, which reduces the activity of MBL-MASP2 complexes occurred in 33% of non-affected women and in 22% primiparae with placental malaria (OR 0.55, permuted p-value 0.020. Conclusions Excessive complement activation is of importance in the pathogenesis of placental malaria by mediating inflammation, coagulation, and endothelial dysfunction. Mutated MBL and MASP2 proteins could have direct intrinsic effects on the susceptibility to placental malaria, in addition to their roles in regulation of downstream complement activation.

  14. Neurons express proteins of the classical complement pathway in Alzheimer disease.

    Science.gov (United States)

    Terai, K; Walker, D G; McGeer, E G; McGeer, P L

    1997-09-26

    Occurrence of the classical pathway complement proteins C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8 and C9 was studied in human hippocampus and temporal cortex by immunohistochemistry and Western blotting. In Alzheimer disease (AD) cases, positive staining for all of these proteins was observed in pyramidal neurons and senile plaques. In control cases, weaker pyramidal neuron staining was observed except for C1q and C1s which were not detected. On Western blots of AD hippocampal extracts, bands corresponding to those detected in normal serum were found for each of the complement proteins. Comparable bands were also detected in normal hippocampal extracts with the exception of C1s which was not observed. The intensity of the bands was generally stronger in AD than in normal extracts, but, in the latter, there was considerable variability between cases and between bands in a single case. These data suggest that pyramidal neurons may be a source of the complement components known to be associated with Alzheimer lesions.

  15. Trypanosoma cruzi calreticulin inhibits the complement lectin pathway activation by direct interaction with L-Ficolin.

    Science.gov (United States)

    Sosoniuk, Eduardo; Vallejos, Gerardo; Kenawy, Hany; Gaboriaud, Christine; Thielens, Nicole; Fujita, Teizo; Schwaeble, Wilhelm; Ferreira, Arturo; Valck, Carolina

    2014-07-01

    Trypanosoma cruzi, the agent of Chagas' disease, the sixth neglected tropical disease worldwide, infects 10-12 million people in Latin America. Differently from T. cruzi epimastigotes, trypomastigotes are complement-resistant and infective. CRPs, T-DAF, sialic acid and lipases explain at least part of this resistance. In vitro, T. cruzi calreticulin (TcCRT), a chaperone molecule that translocates from the ER to the parasite surface: (a) Inhibits the human classical complement activation, by interacting with C1, (b) As a consequence, an increase in infectivity is evident and, (c) It inhibits angiogenesis and tumor growth. We report here that TcCRT also binds to the L-Ficolin collagenous portion, thus inhibiting approximately between 35 and 64% of the human complement lectin pathway activation, initiated by L-Ficolin, a property not shared by H-Ficolin. While L-Ficolin binds to 60% of trypomastigotes and to 24% of epimastigotes, 50% of the former and 4% of the latter display TcCRT on their surfaces. Altogether, these data indicate that TcCRT is a parasite inhibitory receptor for Ficolins. The resulting evasive activities, together with the TcCRT capacity to inhibit C1, with a concomitant increase in infectivity, may represent T. cruzi strategies to inhibit important arms of the innate immune response.

  16. Molluskan Hemocyanins Activate the Classical Pathway of the Human Complement System through Natural Antibodies

    Science.gov (United States)

    Pizarro-Bauerle, Javier; Maldonado, Ismael; Sosoniuk-Roche, Eduardo; Vallejos, Gerardo; López, Mercedes N.; Salazar-Onfray, Flavio; Aguilar-Guzmán, Lorena; Valck, Carolina; Ferreira, Arturo; Becker, María Inés

    2017-01-01

    Molluskan hemocyanins are enormous oxygen-carrier glycoproteins that show remarkable immunostimulatory properties when inoculated in mammals, such as the generation of high levels of antibodies, a strong cellular reaction, and generation of non-specific antitumor immune responses in some types of cancer, particularly for superficial bladder cancer. These proteins have the ability to bias the immune response toward a Th1 phenotype. However, despite all their current uses with beneficial clinical outcomes, a clear mechanism explaining these properties is not available. Taking into account reports of natural antibodies against the hemocyanin of the gastropod Megathura crenulata [keyhole limpet hemocyanin (KLH)] in humans as well as other vertebrate species, we report here for the first time, the presence, in sera from unimmunized healthy donors, of antibodies recognizing, in addition to KLH, two other hemocyanins from gastropods with documented immunomodulatory capacities: Fisurella latimarginata hemocyanin (FLH) and Concholepas concholepas hemocyanin (CCH). Through an ELISA screening, we found IgM and IgG antibodies reactive with these hemocyanins. When the capacity of these antibodies to bind deglycosylated hemocyanins was studied, no decreased interaction was detected. Moreover, in the case of FLH, deglycosylation increased antibody binding. We evaluated through an in vitro complement deposition assay whether these antibodies activated the classical pathway of the human complement system. The results showed that all three hemocyanins and their deglycosylated counterparts elicited this activation, mediated by C1 binding to immunoglobulins. Thus, this work contributes to the understanding on how the complement system could participate in the immunostimulatory properties of hemocyanins, through natural, complement-activating antibodies reacting with these proteins. Although a role for carbohydrates cannot be completely ruled out, in our experimental setting

  17. Borrelia burgdorferi BBK32 Inhibits the Classical Pathway by Blocking Activation of the C1 Complement Complex.

    Directory of Open Access Journals (Sweden)

    Brandon L Garcia

    2016-01-01

    Full Text Available Pathogens that traffic in blood, lymphatics, or interstitial fluids must adopt strategies to evade innate immune defenses, notably the complement system. Through recruitment of host regulators of complement to their surface, many pathogens are able to escape complement-mediated attack. The Lyme disease spirochete, Borrelia burgdorferi, produces a number of surface proteins that bind to factor H related molecules, which function as the dominant negative regulator of the alternative pathway of complement. Relatively less is known about how B. burgdorferi evades the classical pathway of complement despite the observation that some sensu lato strains are sensitive to classical pathway activation. Here we report that the borrelial lipoprotein BBK32 potently and specifically inhibits the classical pathway by binding with high affinity to the initiating C1 complex of complement. In addition, B. burgdorferi cells that produce BBK32 on their surface bind to both C1 and C1r and a serum sensitive derivative of B. burgdorferi is protected from killing via the classical pathway in a BBK32-dependent manner. Subsequent biochemical and biophysical approaches localized the anti-complement activity of BBK32 to its globular C-terminal domain. Mechanistic studies reveal that BBK32 acts by entrapping C1 in its zymogen form by binding and inhibiting the C1 subcomponent, C1r, which serves as the initiating serine protease of the classical pathway. To our knowledge this is the first report of a spirochetal protein acting as a direct inhibitor of the classical pathway and is the only example of a biomolecule capable of specifically and noncovalently inhibiting C1/C1r. By identifying a unique mode of complement evasion this study greatly enhances our understanding of how pathogens subvert and potentially manipulate host innate immune systems.

  18. Borrelia burgdorferi BBK32 Inhibits the Classical Pathway by Blocking Activation of the C1 Complement Complex.

    Science.gov (United States)

    Garcia, Brandon L; Zhi, Hui; Wager, Beau; Höök, Magnus; Skare, Jon T

    2016-01-01

    Pathogens that traffic in blood, lymphatics, or interstitial fluids must adopt strategies to evade innate immune defenses, notably the complement system. Through recruitment of host regulators of complement to their surface, many pathogens are able to escape complement-mediated attack. The Lyme disease spirochete, Borrelia burgdorferi, produces a number of surface proteins that bind to factor H related molecules, which function as the dominant negative regulator of the alternative pathway of complement. Relatively less is known about how B. burgdorferi evades the classical pathway of complement despite the observation that some sensu lato strains are sensitive to classical pathway activation. Here we report that the borrelial lipoprotein BBK32 potently and specifically inhibits the classical pathway by binding with high affinity to the initiating C1 complex of complement. In addition, B. burgdorferi cells that produce BBK32 on their surface bind to both C1 and C1r and a serum sensitive derivative of B. burgdorferi is protected from killing via the classical pathway in a BBK32-dependent manner. Subsequent biochemical and biophysical approaches localized the anti-complement activity of BBK32 to its globular C-terminal domain. Mechanistic studies reveal that BBK32 acts by entrapping C1 in its zymogen form by binding and inhibiting the C1 subcomponent, C1r, which serves as the initiating serine protease of the classical pathway. To our knowledge this is the first report of a spirochetal protein acting as a direct inhibitor of the classical pathway and is the only example of a biomolecule capable of specifically and noncovalently inhibiting C1/C1r. By identifying a unique mode of complement evasion this study greatly enhances our understanding of how pathogens subvert and potentially manipulate host innate immune systems.

  19. C1q, the classical complement pathway protein binds Hirano bodies in Pick's disease.

    Science.gov (United States)

    Singhrao, Sim K

    2013-06-01

    Haematoxylin/Eosin staining was performed to screen for Hirano bodies from the temporal lobe including the hippocampus in 10 Pick's disease cases containing Pick bodies. Although the inclusions were confirmed in 9 out of 10 cases, only 4 out of 10 were particularly enriched with the eosinophilic bodies. These were subjected to immunostaining with anticomplement antibodies and astrocyte marker antiglial fibrillary acidic protein antibody and the HLA class II CR3/43 antibody to visualize microglia. An intraneuronal Hirano body was observed in one case that otherwise contained mainly the extracellular inclusions. In all cases, the extracellular Hirano bodies were seen lying adjacent to soma of neurons within CA1 region of the hippocampus. The extracellular Hirano bodies stained intensely with C1q, the first component of the classical pathway of activation but remained unreactive against antibodies to C4 and the C3 activation products (C3b and iC3b) and the alternative complement pathway component factor B. Hirano bodies also remained negative with the antiglial fibrillary acidic protein for astrocytes and HLA class II antibody CR3/43 for microglia. The results demonstrate that Hirano bodies have strong immunoreactivity to C1q; however, whether other complement components are associated with these inclusions remains to be further investigated.

  20. Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water

    Energy Technology Data Exchange (ETDEWEB)

    Muñoz, Alexandra; Chervona, Yana [New York University School of Medicine, Nelson Institute of Environmental Medicine, Tuxedo, NY (United States); Hall, Megan [Department of Epidemiology, Mailman School of Public Health, Columbia University, New York (United States); Kluz, Thomas [New York University School of Medicine, Nelson Institute of Environmental Medicine, Tuxedo, NY (United States); Gamble, Mary V., E-mail: mvg7@columbia.edu [Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York (United States); Costa, Max, E-mail: Max.Costa@nyumc.org [New York University School of Medicine, Nelson Institute of Environmental Medicine, Tuxedo, NY (United States)

    2015-05-01

    biological implications. • Both sexes exhibit deregulation of cardiovascular and endocrine pathways.

  1. Peptide inhibitor of complement C1 (PIC1, a novel suppressor of classical pathway activation: mechanistic studies and clinical potential

    Directory of Open Access Journals (Sweden)

    Julia A Sharp

    2014-08-01

    Full Text Available The classical pathway of complement plays multiple physiological roles including modulating immunological effectors initiated by adaptive immune responses as well as an essential homeostatic role in the clearance of damaged self-antigens. However, dysregulated classical pathway activation is associated with antibody-initiated, inflammatory diseases processes like cold agglutinin disease (CAD, acute intravascular hemolytic transfusion reaction (AIHTR and acute/hyperacute transplantation rejection. To date, only one putative classical pathway inhibitor, C1 esterase inhibitor (C1-INH, is currently commercially available and its only approved indication is for replacement treatment in hereditary angioedema (HAE, which is predominantly a kinin pathway disease. Given the variety of disease conditions in which the classical pathway is implicated, development of therapeutics that specifically inhibit complement initiation represents a major unmet medical need. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement. In vitro studies have demonstrated that these Peptide Inhibitors of Complement C1 (PIC1 bind to the collagen-like region of the initiator molecule of the classical pathway, C1q. PIC1 binding to C1q blocks activation of the associated serine proteases (C1s-C1r-C1r-C1s and subsequent downstream complement activation. Rational design optimization of PIC1 has resulted in the generation of a highly potent derivative of fifteen amino acids. PIC1 inhibits classical pathway mediated complement activation in ABO incompatibility in vitro as well as inhibiting classical pathway activation in vivo in rats. This review will focus on the pre-clinical development of PIC1 and discuss its potential as a therapeutic in antibody-mediated classical pathway disease, specifically AIHTR.

  2. Interspecies Complementation of the LuxR Family Pathway-Specific Regulator Involved in Macrolide Biosynthesis.

    Science.gov (United States)

    Mo, SangJoon; Yoon, Yeo Joon

    2016-01-01

    PikD is a widely known pathway-specific regulator for controlling pikromycin production in Streptomyces venezuelae ATCC 15439, which is a representative of the large ATP-binding regulator of the LuxR family (LAL) in Streptomyces sp. RapH and FkbN also belong to the LAL family of transcriptional regulators, which show greatest homology with the ATP-binding motif and helix-turn-helix DNA-binding motif of PikD. Overexpression of pikD and heterologous expression of rapH and fkbN led to enhanced production of pikromycin by approximately 1.8-, 1.6-, and 1.6-fold in S. venezuelae, respectively. Cross-complementation of rapH and fkbN in the pikD deletion mutant (ΔpikD) restored pikromycin and derived macrolactone production. Overall, these results show that heterologous expression of rapH and fkbN leads to the overproduction of pikromycin and its congeners from the pikromycin biosynthetic pathway in S. venezuelae, and they have the same functionality as the pathwayspecific transcriptional activator for the pikromycin biosynthetic pathway in the ΔpikD strain. These results also show extensive "cross-communication" between pathway-specific regulators of streptomycetes and suggest revision of the current paradigm for pathwayspecific versus global regulation of secondary metabolism in Streptomyces species.

  3. Toward a structure-based comprehension of the lectin pathway of complement.

    Science.gov (United States)

    Kjaer, Troels R; Thiel, Steffen; Andersen, Gregers R

    2013-12-15

    To initiate the lectin pathway of complement pattern recognition molecules bind to surface-linked carbohydrates or acetyl groups on pathogens or damaged self-tissue. This leads to activation of the serine proteases MASP-1 and MASP-2 resulting in deposition of C4 on the activator and assembly of the C3 convertase. In addition MASP-3 and the non-catalytic MAp19 and MAp44 presumably play regulatory functions, but the exact function of the MASP-3 protease remains to be established. Recent functional studies have significantly advanced our understanding of the molecular events occurring as activation progresses from pattern recognition to convertase assembly. Furthermore, atomic structures derived by crystallography or solution scattering of most proteins acting in the lectin pathway and two key complexes have become available. Here we integrate the current functional and structural knowledge concerning the lectin pathway proteins and derive overall models for their glycan bound complexes. These models are used to discuss cis- versus trans-activation of MASP proteases and the geometry of C4 deposition occurring on glycans in the lectin pathway.

  4. A Targeted Inhibitor of the Alternative Complement Pathway Accelerates Recovery From Smoke-Induced Ocular Injury

    Science.gov (United States)

    Woodell, Alex; Jones, Bryan W.; Williamson, Tucker; Schnabolk, Gloriane; Tomlinson, Stephen; Atkinson, Carl; Rohrer, Bärbel

    2016-01-01

    Purpose Morphologic and genetic evidence exists that an overactive complement system driven by the complement alternative pathway (AP) is involved in pathogenesis of age-related macular degeneration (AMD). Smoking is the only modifiable risk factor for AMD. As we have shown that smoke-related ocular pathology can be prevented in mice that lack an essential activator of AP, we ask here whether this pathology can be reversed by increasing inhibition in AP. Methods Mice were exposed to either cigarette smoke (CS) or filtered air (6 hours/day, 5 days/week, 6 months). Smoke-exposed animals were then treated with the AP inhibitor (CR2-fH) or vehicle control (PBS) for the following 3 months. Spatial frequency and contrast sensitivity were assessed by optokinetic response paradigms at 6 and 9 months; additional readouts included assessment of retinal morphology by electron microscopy (EM) and gene expression analysis by quantitative RT-PCR. Results The CS mice treated with CR2-fH showed significant improvement in contrast threshold compared to PBS-treated mice, whereas spatial frequency was unaffected by CS or pharmacologic intervention. Treatment with CR2-fH in CS animals reversed thinning of the retina observed in PBS-treated mice as analyzed by spectral-domain optical coherence tomography, and reversed most morphologic changes in RPE and Bruch's membrane seen in CS animals by EM. Conclusions Taken together, these findings suggest that AP inhibitors not only prevent, but have the potential to accelerate the clearance of complement-mediated ocular injury. Improving our understanding of the regulation of the AP is paramount to developing novel treatment approaches for AMD. PMID:27064393

  5. Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases

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    Katherine eLintner

    2016-02-01

    Full Text Available The complement system consists of effector proteins, regulators, and receptors that participate in host defense against pathogens. Activation of the complement system, via the classical pathway (CP, has long been recognized in immune complex-mediated tissue injury, most notably systemic lupus erythematosus (SLE. Paradoxically, a complete deficiency of an early component of the CP, as evidenced by homozygous genetic deficiencies reported in human, are strongly associated with the risk of developing SLE or a lupus-like disease. Similarly, isotype deficiency attributable to a gene copy number variation, and/or the presence of autoantibodies directed against a CP component or a regulatory protein that result in an acquired deficiency are relatively common in SLE patients. Applying accurate assay methodologies with rigorous data validations, low gene copy numbers of total C4, heterozygous and homozygous deficiencies of C4A have been shown as medium to large effect size risk factors, while high copy numbers of total C4 or C4A as prevalent protective factors, of European and East-Asian SLE. Here, we summarize the current knowledge related to genetic deficiency and insufficiency, and acquired protein alterations for C1q, C1r, C1s, C4A/C4B, and C2 in disease pathogenesis and prognosis of SLE, and, briefly, for other systemic autoimmune diseases. As the complement system is increasingly found to be associated with autoimmune diseases, it has become an attractive therapeutic target. We highlight the recent developments and offer a balanced perspective concerning future investigations and therapeutic applications with a focus on early components of the CP in human systemic autoimmune diseases.

  6. A novel targeted inhibitor of the alternative pathway of complement and its therapeutic application in ischemia/reperfusion injury.

    Science.gov (United States)

    Huang, Yuxiang; Qiao, Fei; Atkinson, Carl; Holers, V Michael; Tomlinson, Stephen

    2008-12-01

    Bioavailability and therapeutic efficacy of soluble Crry, a mouse inhibitor of all complement activation pathways, is significantly enhanced when linked to a fragment of complement receptor 2 (CR2), a receptor that targets C3 activation products. In this study, we characterize alternative pathway-specific inhibitors consisting of a single or dimeric N-terminal region of mouse factor H (fH; short consensus repeats 1-5) linked to the same CR2 fragment (CR2-fH and CR2-fHfH). Both CR2-fH and CR2-fHfH were highly effective at inhibiting the alternative pathway in vitro and demonstrated a higher specific activity than CR2-Crry. CR2-fH was also more effective than endogenous serum fH in blocking target deposition of C3. Target binding and complement inhibitory activity of CR2-fH/CR2-fHfH was dependent on CR2- and C3-mediated interactions. The alternative pathway of complement plays a role in intestine ischemia/reperfusion injury. However, serum fH fails to provide protection against intestine ischemia/reperfusion injury although it can bind to and provide cell surfaces with protection from complement and is present in plasma at a high concentration. In a mouse model, CR2-fH and CR2-fHfH provided complete protection from local (intestine) and remote (lung) injury. CR2-fH targeted to the site of local injury and greatly reduced levels of tissue C3 deposition. Thus, the targeting mechanism significantly enhances alternative pathway-specific complement inhibitory activity of the N-terminal domain of fH and has the potential to reduce side effects that may be associated with systemic complement blockade. The data further indicate alternative pathway dependence for local and remote injury following intestinal ischemia/reperfusion in a clinically relevant therapeutic paradigm.

  7. Alternative complement pathway and factor B activities in rats with altered blood levels of thyroid hormone

    Energy Technology Data Exchange (ETDEWEB)

    Bitencourt, C.S. [Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Duarte, C.G.; Azzolini, A.E.C.S.; Assis-Pandochi, A.I. [Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil)

    2012-03-02

    Evaluating the activity of the complement system under conditions of altered thyroid hormone levels might help elucidate the role of complement in triggering autoimmune processes. Here, we investigated alternative pathway (AP) activity in male Wistar rats (180 ± 10 g) after altering their thyroid hormone levels by treatment with triiodothyronine (T3), propylthiouracil (PTU) or thyroidectomy. T3 and thyroxine (T4) levels were determined by chemiluminescence assays. Hemolytic assays were performed to evaluate the lytic activity of the AP. Factor B activity was evaluated using factor B-deficient serum. An anti-human factor B antibody was used to measure factor B levels in serum by radial immunodiffusion. T3 measurements in thyroidectomized animals or animals treated with PTU demonstrated a significant reduction in hormone levels compared to control. The results showed a reduction in AP lytic activity in rats treated with increasing amounts of T3 (1, 10, or 50 µg). Factor B activity was also decreased in the sera of hyperthyroid rats treated with 1 to 50 µg T3. Additionally, treating rats with 25 µg T3 significantly increased factor B levels in their sera (P < 0.01). In contrast, increased factor B concentration and activity (32%) were observed in hypothyroid rats. We conclude that alterations in thyroid hormone levels affect the activity of the AP and factor B, which may in turn affect the roles of AP and factor B in antibody production.

  8. Alternative complement pathway and factor B activities in rats with altered blood levels of thyroid hormone

    Directory of Open Access Journals (Sweden)

    C.S. Bitencourt

    2012-03-01

    Full Text Available Evaluating the activity of the complement system under conditions of altered thyroid hormone levels might help elucidate the role of complement in triggering autoimmune processes. Here, we investigated alternative pathway (AP activity in male Wistar rats (180 ± 10 g after altering their thyroid hormone levels by treatment with triiodothyronine (T3, propylthiouracil (PTU or thyroidectomy. T3 and thyroxine (T4 levels were determined by chemiluminescence assays. Hemolytic assays were performed to evaluate the lytic activity of the AP. Factor B activity was evaluated using factor B-deficient serum. An anti-human factor B antibody was used to measure factor B levels in serum by radial immunodiffusion. T3 measurements in thyroidectomized animals or animals treated with PTU demonstrated a significant reduction in hormone levels compared to control. The results showed a reduction in AP lytic activity in rats treated with increasing amounts of T3 (1, 10, or 50 µg. Factor B activity was also decreased in the sera of hyperthyroid rats treated with 1 to 50 µg T3. Additionally, treating rats with 25 µg T3 significantly increased factor B levels in their sera (P < 0.01. In contrast, increased factor B concentration and activity (32% were observed in hypothyroid rats. We conclude that alterations in thyroid hormone levels affect the activity of the AP and factor B, which may in turn affect the roles of AP and factor B in antibody production.

  9. Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB–mediated pathogenic pathways

    Science.gov (United States)

    Swarup, Vivek; Phaneuf, Daniel; Dupré, Nicolas; Petri, Susanne; Strong, Michael; Kriz, Jasna

    2011-01-01

    TDP-43 (TAR DNA-binding protein 43) inclusions are a hallmark of amyotrophic lateral sclerosis (ALS). In this study, we report that TDP-43 and nuclear factor κB (NF-κB) p65 messenger RNA and protein expression is higher in spinal cords in ALS patients than healthy individuals. TDP-43 interacts with and colocalizes with p65 in glial and neuronal cells from ALS patients and mice expressing wild-type and mutant TDP-43 transgenes but not in cells from healthy individuals or nontransgenic mice. TDP-43 acted as a co-activator of p65, and glial cells expressing higher amounts of TDP-43 produced more proinflammatory cytokines and neurotoxic mediators after stimulation with lipopolysaccharide or reactive oxygen species. TDP-43 overexpression in neurons also increased their vulnerability to toxic mediators. Treatment of TDP-43 mice with Withaferin A, an inhibitor of NF-κB activity, reduced denervation in the neuromuscular junction and ALS disease symptoms. We propose that TDP-43 deregulation contributes to ALS pathogenesis in part by enhancing NF-κB activation and that NF-κB may constitute a therapeutic target for the disease. PMID:22084410

  10. CR2-mediated activation of the complement alternative pathway results in formation of membrane attack complexes on human B lymphocytes

    DEFF Research Database (Denmark)

    Nielsen, C H; Marquart, H V; Prodinger, W M;

    2001-01-01

    Normal human B lymphocytes activate the alternative pathway of complement via complement receptor type 2 (CR2, CD21), that binds hydrolysed C3 (iC3) and thereby promotes the formation of a membrane-bound C3 convertase. We have investigated whether this might lead to the generation of a C5...... convertase and consequent formation of membrane attack complexes (MAC). Deposition of C3 fragments and MAC was assessed on human peripheral B lymphocytes in the presence of 30% autologous serum containing 4.4 mM MgCl2/20 mM EGTA, which abrogates the classical pathway of complement without affecting...... the alternative pathway. Blockade of the CR2 ligand-binding site with the monoclonal antibody FE8 resulted in 56 +/- 13% and 71 +/- 9% inhibition of the C3-fragment and MAC deposition, respectively, whereas the monoclonal antibody HB135, directed against an irrelevant CR2 epitope, had no effect. Blockade...

  11. Reduced neuronal cell death after experimental brain injury in mice lacking a functional alternative pathway of complement activation

    Directory of Open Access Journals (Sweden)

    Huber-Lang Markus

    2006-07-01

    Full Text Available Abstract Background Neuroprotective strategies for prevention of the neuropathological sequelae of traumatic brain injury (TBI have largely failed in translation to clinical treatment. Thus, there is a substantial need for further understanding the molecular mechanisms and pathways which lead to secondary neuronal cell death in the injured brain. The intracerebral activation of the complement cascade was shown to mediate inflammation and tissue destruction after TBI. However, the exact pathways of complement activation involved in the induction of posttraumatic neurodegeneration have not yet been assessed. In the present study, we investigated the role of the alternative complement activation pathway in contributing to neuronal cell death, based on a standardized TBI model in mice with targeted deletion of the factor B gene (fB-/-, a "key" component required for activation of the alternative complement pathway. Results After experimental TBI in wild-type (fB+/+ mice, there was a massive time-dependent systemic complement activation, as determined by enhanced C5a serum levels for up to 7 days. In contrast, the extent of systemic complement activation was significantly attenuated in fB-/- mice (P fB-/- vs. fB+/+; t = 4 h, 24 h, and 7 days after TBI. TUNEL histochemistry experiments revealed that posttraumatic neuronal cell death was clearly reduced for up to 7 days in the injured brain hemispheres of fB-/- mice, compared to fB+/+ littermates. Furthermore, a strong upregulation of the anti-apoptotic mediator Bcl-2 and downregulation of the pro-apoptotic Fas receptor was detected in brain homogenates of head-injured fB-/- vs. fB+/+ mice by Western blot analysis. Conclusion The alternative pathway of complement activation appears to play a more crucial role in the pathophysiology of TBI than previously appreciated. This notion is based on the findings of (a the significant attenuation of overall complement activation in head-injured fB-/- mice, as

  12. DMPD: Complement-mediated phagocytosis--the role of Syk. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16754322 Complement-mediated phagocytosis--the role of Syk. Tohyama Y, Yamamura H. ...IUBMB Life. 2006 May-Jun;58(5-6):304-8. (.png) (.svg) (.html) (.csml) Show Complement-mediated phagocytosis-...-the role of Syk. PubmedID 16754322 Title Complement-mediated phagocytosis--the role of Syk. Authors Tohyama

  13. Alternative Pathway Dysregulation and the Conundrum of Complement Activation by IgG4 Immune Complexes in Membranous Nephropathy

    Science.gov (United States)

    Borza, Dorin-Bogdan

    2016-01-01

    Membranous nephropathy (MN), a major cause of nephrotic syndrome, is a non-inflammatory immune kidney disease mediated by IgG antibodies that form glomerular subepithelial immune complexes. In primary MN, autoantibodies target proteins expressed on the podocyte surface, often phospholipase A2 receptor (PLA2R1). Pathology is driven by complement activation, leading to podocyte injury and proteinuria. This article overviews the mechanisms of complement activation and regulation in MN, addressing the paradox that anti-PLA2R1 and other antibodies causing primary MN are predominantly (but not exclusively) IgG4, an IgG subclass that does not fix complement. Besides immune complexes, alterations of the glomerular basement membrane (GBM) in MN may lead to impaired regulation of the alternative pathway (AP). The AP amplifies complement activation on surfaces insufficiently protected by complement regulatory proteins. Whereas podocytes are protected by cell-bound regulators, the GBM must recruit plasma factor H, which inhibits the AP on host surfaces carrying certain polyanions, such as heparan sulfate (HS) chains. Because HS chains present in the normal GBM are lost in MN, we posit that the local complement regulation by factor H may be impaired as a result. Thus, the loss of GBM HS in MN creates a micro-environment that promotes local amplification of complement activation, which in turn may be initiated via the classical or lectin pathways by subsets of IgG in immune complexes. A detailed understanding of the mechanisms of complement activation and dysregulation in MN is important for designing more effective therapies. PMID:27199983

  14. A metalloproteinase karilysin present in the majority of Tannerella forsythia isolates inhibits all pathways of the complement system

    DEFF Research Database (Denmark)

    Jusko, Monika; Potempa, Jan; Karim, Abdulkarim Y

    2012-01-01

    Tannerella forsythia is a poorly studied pathogen despite being one of the main causes of periodontitis, which is an inflammatory disease of the supporting structures of the teeth. We found that despite being recognized by all complement pathways, T. forsythia is resistant to killing by human com...

  15. Transcriptome profiling identifies genes and pathways deregulated upon floxuridine treatment in colorectal cancer cells harboring GOF mutant p53

    Directory of Open Access Journals (Sweden)

    Arindam Datta

    2016-06-01

    Full Text Available Mutation in TP53 is a common genetic alteration in human cancers. Certain tumor associated p53 missense mutants acquire gain-of-function (GOF properties and confer oncogenic phenotypes including enhanced chemoresistance. The colorectal cancers (CRC harboring mutant p53 are generally aggressive in nature and difficult to treat. To identify a potential gene expression signature of GOF mutant p53-driven acquired chemoresistance in CRC, we performed transcriptome profiling of floxuridine (FUdR treated SW480 cells expressing mutant p53R273H (GEO#: GSE77533. We obtained several genes differentially regulated between FUdR treated and untreated cells. Further, functional characterization and pathway analysis revealed significant enrichment of crucial biological processes and pathways upon FUdR treatment in SW480 cells. Our data suggest that in response to chemotherapeutics treatment, cancer cells with GOF mutant p53 can modulate key cellular pathways to withstand the cytotoxic effect of the drugs. The genes and pathways identified in the present study can be further validated and targeted for better chemotherapy response in colorectal cancer patients harboring mutant p53.

  16. The alternative complement pathway aids in vascular regression during the early stages of a murine model of proliferative retinopathy.

    Science.gov (United States)

    Kim, Clifford; Smith, Kaylee E; Castillejos, Alexandra; Diaz-Aguilar, Daniel; Saint-Geniez, Magali; Connor, Kip M

    2016-03-01

    Proliferative retinopathic diseases often progress in 2 phases: initial regression of retinal vasculature (phase 1) followed by subsequent neovascularization (NV) (phase 2). The immune system has been shown to aid in vascular pruning in such retinopathies; however, little is known about the role of the alternative complement pathway in the initial vascular regression phase. Using a mouse model of oxygen-induced retinopathy (OIR), we observed that alternative complement pathway-deficient mice (Fb(-/-)) exhibited a mild decrease in vascular loss at postnatal day (P)8 compared with age- and strain-matched controls (P = 0.035). Laser capture microdissection was used to isolate the retinal blood vessels. Expression of the complement inhibitors Cd55 and Cd59 was significantly decreased in blood vessels isolated from hyperoxic retinas compared with those from normoxic control mice. Vegf expression was measured at P8 and found to be significantly lower in OIR mice than in normoxic control mice (P = 0.0048). Further examination of specific Vegf isoform expression revealed a significant decrease in Vegf120 (P = 0.00032) and Vegf188 (P = 0.0092). In conjunction with the major modulating effects of Vegf during early retinal vascular development, our data suggest a modest involvement of the alternative complement pathway in targeting vessels for regression in the initial vaso-obliteration stage of OIR. © The Author(s).

  17. Down-regulation of complement receptors on the surface of host monocyte even as in vitro complement pathway blocking interferes in dengue infection.

    Science.gov (United States)

    Marinho, Cintia Ferreira; Azeredo, Elzinandes Leal; Torrentes-Carvalho, Amanda; Marins-Dos-Santos, Alessandro; Kubelka, Claire Fernandes; de Souza, Luiz José; Cunha, Rivaldo Venâncio; de-Oliveira-Pinto, Luzia Maria

    2014-01-01

    In dengue virus (DENV) infection, complement system (CS) activation appears to have protective and pathogenic effects. In severe dengue fever (DF), the levels of DENV non-structural-1 protein and of the products of complement activation, including C3a, C5a and SC5b-9, are higher before vascular leakage occurs, supporting the hypothesis that complement activation contributes to unfavourable outcomes. The clinical manifestations of DF range from asymptomatic to severe and even fatal. Here, we aimed to characterise CS by their receptors or activation product, in vivo in DF patients and in vitro by DENV-2 stimulation on monocytes. In comparison with healthy controls, DF patients showed lower expression of CR3 (CD11b), CR4 (CD11c) and, CD59 on monocytes. The DF patients who were high producers of SC5b-9 were also those that showed more pronounced bleeding or vascular leakage. Those findings encouraged us to investigate the role of CS in vitro, using monocytes isolated from healthy subjects. Prior blocking with CR3 alone (CD11b) or CR3 (CD11b/CD18) reduced viral infection, as quantified by the levels of intracellular viral antigen expression and soluble DENV non-structural viral protein. However, we found that CR3 alone (CD11b) or CR3 (CD11b/CD18) blocking did not influence major histocompatibility complex presentation neither active caspase-1 on monocytes, thus probably ruling out inflammasome-related mechanisms. Although it did impair the secretion of tumour necrosis factor alpha and interferon alpha. Our data provide strategies of blocking CR3 (CD11b) pathways could have implications for the treatment of viral infection by antiviral-related mechanisms.

  18. Down-regulation of complement receptors on the surface of host monocyte even as in vitro complement pathway blocking interferes in dengue infection.

    Directory of Open Access Journals (Sweden)

    Cintia Ferreira Marinho

    Full Text Available In dengue virus (DENV infection, complement system (CS activation appears to have protective and pathogenic effects. In severe dengue fever (DF, the levels of DENV non-structural-1 protein and of the products of complement activation, including C3a, C5a and SC5b-9, are higher before vascular leakage occurs, supporting the hypothesis that complement activation contributes to unfavourable outcomes. The clinical manifestations of DF range from asymptomatic to severe and even fatal. Here, we aimed to characterise CS by their receptors or activation product, in vivo in DF patients and in vitro by DENV-2 stimulation on monocytes. In comparison with healthy controls, DF patients showed lower expression of CR3 (CD11b, CR4 (CD11c and, CD59 on monocytes. The DF patients who were high producers of SC5b-9 were also those that showed more pronounced bleeding or vascular leakage. Those findings encouraged us to investigate the role of CS in vitro, using monocytes isolated from healthy subjects. Prior blocking with CR3 alone (CD11b or CR3 (CD11b/CD18 reduced viral infection, as quantified by the levels of intracellular viral antigen expression and soluble DENV non-structural viral protein. However, we found that CR3 alone (CD11b or CR3 (CD11b/CD18 blocking did not influence major histocompatibility complex presentation neither active caspase-1 on monocytes, thus probably ruling out inflammasome-related mechanisms. Although it did impair the secretion of tumour necrosis factor alpha and interferon alpha. Our data provide strategies of blocking CR3 (CD11b pathways could have implications for the treatment of viral infection by antiviral-related mechanisms.

  19. Antibody directs properdin-dependent activation of the complement alternative pathway in a mouse model of abdominal aortic aneurysm.

    Science.gov (United States)

    Zhou, Hui-Fang; Yan, Huimin; Stover, Cordula M; Fernandez, Tamara Montes; Rodriguez de Cordoba, Santiago; Song, Wen-Chao; Wu, Xiaobo; Thompson, Robert W; Schwaeble, Wilhelm J; Atkinson, John P; Hourcade, Dennis E; Pham, Christine T N

    2012-02-14

    Abdominal aortic aneurysm (AAA) is a complex inflammatory vascular disease. There are currently limited treatment options for AAA when surgery is inapplicable. Therefore, insights into molecular mechanisms underlying AAA pathogenesis may reveal therapeutic targets that could be manipulated pharmacologically or biologically to halt disease progression. Using an elastase-induced AAA mouse model, we previously established that the complement alternative pathway (AP) plays a critical role in the development of AAA. However, the mechanism by which complement AP is initiated remains undefined. The complement protein properdin, traditionally viewed as a positive regulator of the AP, may also initiate complement activation by binding directly to target surfaces. In this study, we sought to determine whether properdin serves as a focal point for the initiation of the AP complement activation in AAA. Using a properdin loss of function mutation in mice and a mutant form of the complement factor B protein that produces a stable, properdin-free AP C3 convertase, we show that properdin is required for the development of elastase-induced AAA in its primary role as a convertase stabilizer. Unexpectedly, we find that, in AAA, natural IgG antibodies direct AP-mediated complement activation. The absence of IgG abrogates C3 deposition in elastase-perfused aortic wall and protects animals from AAA development. We also determine that blockade of properdin activity prevents aneurysm formation. These results indicate that an innate immune response to self-antigens activates the complement system and initiates the inflammatory cascade in AAA. Moreover, the study suggests that properdin-targeting strategies may halt aneurysmal growth.

  20. Classical complement pathway activation in the kidneys of women with preeclampsia

    NARCIS (Netherlands)

    Penning, Marlies; Chua, Jamie S.; Van Kooten, Cees; Zandbergen, Malu; Buurma, Aletta; Schutte, Joke; Bruijn, Jan Anthonie; Khankin, Eliyahu V.; Bloemenkamp, Kitty; Karumanchi, S. Ananth; Baelde, Hans

    2015-01-01

    A growing body of evidence suggests that complement dysregulation plays a role in the pathogenesis of preeclampsia. The kidney is one of the major organs affected in preeclampsia. Because the kidney is highly susceptible to complement activation, we hypothesized that preeclampsia is associated with

  1. Genomic deregulation of the E2F/Rb pathway leads to activation of the oncogene EZH2 in small cell lung cancer.

    Directory of Open Access Journals (Sweden)

    Bradley P Coe

    Full Text Available Small cell lung cancer (SCLC is a highly aggressive lung neoplasm with extremely poor clinical outcomes and no approved targeted treatments. To elucidate the mechanisms responsible for driving the SCLC phenotype in hopes of revealing novel therapeutic targets, we studied copy number and methylation profiles of SCLC. We found disruption of the E2F/Rb pathway was a prominent feature deregulated in 96% of the SCLC samples investigated and was strongly associated with increased expression of EZH2, an oncogene and core member of the polycomb repressive complex 2 (PRC2. Through its catalytic role in the PRC2 complex, EZH2 normally functions to epigenetically silence genes during development, however, it aberrantly silences genes in human cancers. We provide evidence to support that EZH2 is functionally active in SCLC tumours, exerts pro-tumourigenic functions in vitro, and is associated with aberrant methylation profiles of PRC2 target genes indicative of a "stem-cell like" hypermethylator profile in SCLC tumours. Furthermore, lentiviral-mediated knockdown of EZH2 demonstrated a significant reduction in the growth of SCLC cell lines, suggesting EZH2 has a key role in driving SCLC biology. In conclusion, our data confirm the role of EZH2 as a critical oncogene in SCLC, and lend support to the prioritization of EZH2 as a potential therapeutic target in clinical disease.

  2. Lectin Pathway of Complement Activation Is Associated with Vulnerability of Atherosclerotic Plaques

    Science.gov (United States)

    Fumagalli, Stefano; Perego, Carlo; Zangari, Rosalia; De Blasio, Daiana; Oggioni, Marco; De Nigris, Francesca; Snider, Francesco; Garred, Peter; Ferrante, Angela M. R.; De Simoni, Maria-Grazia

    2017-01-01

    Inflammatory mechanisms may be involved in atherosclerotic plaque rupture. By using a novel histology-based method to quantify plaque instability here, we assess whether lectin pathway (LP) of complement activation, a major inflammation arm, could represent an index of plaque instability. Plaques from 42 consecutive patients undergoing carotid endarterectomy were stained with hematoxylin-eosin and the lipid core, cholesterol clefts, hemorrhagic content, thickness of tunica media, and intima, including or not infiltration of cellular debris and cholesterol, were determined. The presence of ficolin-1, -2, and -3 and mannose-binding lectin (MBL), LP initiators, was assessed in the plaques by immunofluorescence and in plasma by ELISA. LP activation was assessed in plasma by functional in vitro assays. Patients presenting low stenosis (≤75%) had higher hemorrhagic content than those with high stenosis (>75%), indicating increased erosion. Increased hemorrhagic content and tunica media thickness, as well as decreased lipid core and infiltrated content were associated with vulnerable plaques and therefore used to establish a plaque vulnerability score that allowed to classify patients according to plaque vulnerability. Ficolins and MBL were found both in plaques’ necrotic core and tunica media. Patients with vulnerable plaques showed decreased plasma levels and intraplaque deposition of ficolin-2. Symptomatic patients experiencing a transient ischemic attack had lower plasma levels of ficolin-1. We show that the LP initiators are present within the plaques and their circulating levels change in atherosclerotic patients. In particular, we show that decreased ficolin-2 levels are associated with rupture-prone vulnerable plaques, indicating its potential use as marker for cardiovascular risk assessment in atherosclerotic patients. PMID:28360913

  3. Role of complement in host-microbe homeostasis of the periodontium.

    Science.gov (United States)

    Hajishengallis, George; Abe, Toshiharu; Maekawa, Tomoki; Hajishengallis, Evlambia; Lambris, John D

    2013-02-01

    Complement plays a key role in immunity and inflammation through direct effects on immune cells or via crosstalk and regulation of other host signaling pathways. Deregulation of these finely balanced complement activities can link infection to inflammatory tissue damage. Periodontitis is a polymicrobial community-induced chronic inflammatory disease that can destroy the tooth-supporting tissues. In this review, we summarize and discuss evidence that complement is involved in the dysbiotic transformation of the periodontal microbiota and in the inflammatory process that leads to the destruction of periodontal bone. Recent insights into the mechanisms of complement involvement in periodontitis have additionally provided likely targets for therapeutic intervention against this oral disease.

  4. Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells.

    Science.gov (United States)

    Dolatshad, H; Pellagatti, A; Fernandez-Mercado, M; Yip, B H; Malcovati, L; Attwood, M; Przychodzen, B; Sahgal, N; Kanapin, A A; Lockstone, H; Scifo, L; Vandenberghe, P; Papaemmanuil, E; Smith, C W J; Campbell, P J; Ogawa, S; Maciejewski, J P; Cazzola, M; Savage, K I; Boultwood, J

    2015-05-01

    The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34(+) cells from MDS patients with SF3B1 mutations using RNA sequencing. Genes significantly differentially expressed at the transcript and/or exon level in SF3B1 mutant compared with wild-type cases include genes that are involved in MDS pathogenesis (ASXL1 and CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7 and SLC25A37) and RNA splicing/processing (PRPF8 and HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expression/splicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34(+) cells. Our data indicate that SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processes/pathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link.

  5. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus

    Science.gov (United States)

    Di Nicolantonio, Federica; Arena, Sabrina; Tabernero, Josep; Grosso, Stefano; Molinari, Francesca; Macarulla, Teresa; Russo, Mariangela; Cancelliere, Carlotta; Zecchin, Davide; Mazzucchelli, Luca; Sasazuki, Takehiko; Shirasawa, Senji; Geuna, Massimo; Frattini, Milo; Baselga, José; Gallicchio, Margherita; Biffo, Stefano; Bardelli, Alberto

    2010-01-01

    Personalized cancer medicine is based on the concept that targeted therapies are effective on subsets of patients whose tumors carry specific molecular alterations. Several mammalian target of rapamycin (mTOR) inhibitors are in preclinical or clinical trials for cancers, but the molecular basis of sensitivity or resistance to these inhibitors among patients is largely unknown. Here we have identified oncogenic variants of phosphoinositide-3-kinase, catalytic, α polypeptide (PIK3CA) and KRAS as determinants of response to the mTOR inhibitor everolimus. Human cancer cells carrying alterations in the PI3K pathway were responsive to everolimus, both in vitro and in vivo, except when KRAS mutations occurred concomitantly or were exogenously introduced. In human cancer cells with mutations in both PIK3CA and KRAS, genetic ablation of mutant KRAS reinstated response to the drug. Consistent with these data, PIK3CA mutant cells, but not KRAS mutant cells, displayed everolimus-sensitive translation. Importantly, in a cohort of metastatic cancer patients, the presence of oncogenic KRAS mutations was associated with lack of benefit after everolimus therapy. Thus, our results demonstrate that alterations in the KRAS and PIK3CA genes may represent biomarkers to optimize treatment of patients with mTOR inhibitors. PMID:20664172

  6. A metalloproteinase karilysin present in the majority of Tannerella forsythia isolates inhibits all pathways of the complement system.

    Science.gov (United States)

    Jusko, Monika; Potempa, Jan; Karim, Abdulkarim Y; Ksiazek, Miroslaw; Riesbeck, Kristian; Garred, Peter; Eick, Sigrun; Blom, Anna M

    2012-03-01

    Tannerella forsythia is a poorly studied pathogen despite being one of the main causes of periodontitis, which is an inflammatory disease of the supporting structures of the teeth. We found that despite being recognized by all complement pathways, T. forsythia is resistant to killing by human complement, which is present at up to 70% of serum concentration in gingival crevicular fluid. Incubation of human serum with karilysin, a metalloproteinase of T. forsythia, resulted in a decrease in bactericidal activity of the serum. T. forsythia strains expressing karilysin at higher levels were more resistant than low-expressing strains. Furthermore, the low-expressing strain was significantly more opsonized with activated complement factor 3 and membrane attack complex from serum compared with the other strains. The high-expressing strain was more resistant to killing in human blood. The protective effect of karilysin against serum bactericidal activity was attributable to its ability to inhibit complement at several stages. The classical and lectin complement pathways were inhibited because of the efficient degradation of mannose-binding lectin, ficolin-2, ficolin-3, and C4 by karilysin, whereas inhibition of the terminal pathway was caused by degradation of C5. Interestingly, karilysin was able to release biologically active C5a peptide in human plasma and induce migration of neutrophils. Importantly, we detected the karilysin gene in >90% of gingival crevicular fluid samples containing T. forsythia obtained from patients with periodontitis. Taken together, the newly characterized karilysin appears to be an important virulence factor of T. forsythia and might have several important implications for immune evasion.

  7. JAK2-STAT3 pathway regulates the expression of complement factor B in autosomal dominant polycystic kidney disease

    Institute of Scientific and Technical Information of China (English)

    周晨晨

    2014-01-01

    Objective To investigate the role of JAK2-STAT3pathway in the expression of complement factor B(CFB)in autosomal dominant polycystic kidney disease(ADP KD).Methods Renal tissue samples of patients with ADPKD after nephrectomy were collected.Normal rena tissue samples as control were taken from patients afte radical nephrectomy.Renal tissue samples of Han:SPRD Cy/+rats(ADPKD model)and wild-type Han:

  8. FRAGMENT Bb: EVIDENCE FOR ACTIVATION OF THE ALTERNATIVE PATHWAY OF THE COMPLEMENT SYSTEM IN PREGNANT WOMEN WITH ACUTE PYELONEPHRITIS

    Science.gov (United States)

    Soto, Eleazar; Romero, Roberto; Vaisbuch, Edi; Erez, Offer; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Dong, Zhong; Chaiworapongsa, Tinnakorn; Yeo, Lami; Mittal, Pooja; Hassan, Sonia S.

    2010-01-01

    OBJECTIVE Pyelonephritis during pregnancy is associated with a more severe course than in the non-pregnant state. This has been attributed to an increased susceptibility of pregnant women to microbial products. The complement system is part of innate immunity and its alternative pathway is activated mainly by microorganisms. The purpose of this study was to determine if activation of the alternative pathway of the complement system (determined by maternal fragment Bb concentrations) occurs in pregnant women with acute pyelonephritis. METHODS This cross-sectional study included the following groups: 1) normal pregnant women (n=62); and 2) pregnant women with pyelonephritis (n=38). Maternal plasma Fragment Bb concentrations were determined by ELISA. Non-parametric statistics were used for analyses. RESULTS 1) Pregnant women with pyelonephritis had a higher median plasma concentration of fragment Bb than those with a normal pregnancy (1.3 μg/ml, IQR: 1.1-1.9 vs. 0.8 μg/m, IQR: 0.7-0.9; ppyelonephritis who had a positive blood culture and those with a negative blood culture (1.4 μg/ml, IQR: 1.1-3.5 vs. 1.3 μg/ml, IQR: 1.1-1.9; p=0.2). CONCLUSIONS Pregnant women with acute pyelonephritis have evidence of activation of the alternative pathway of the complement system, regardless of the presence or absence of a positive blood culture. PMID:20218820

  9. Activation capacity of the alternative and classic complement pathways in patients operated on for colorectal cancer

    DEFF Research Database (Denmark)

    Zimmermann-Nielsen, Erik; Iversen, Lene H; Svehag, Sven-Erik;

    2002-01-01

    . Significant differences in C3 activation capacities were observed between cancer patients that were related to Dukes stage and in patients with and without buffy coat-depleted red cells suspended in saline, adenine, glucose, and mannitol transfusion, infectious events, and deep venous thromboembolism......PURPOSE: Tumor cells may suppress activation of the host's complement system, and the functional state of the complement system may be a prognostic marker of outcome in patients with malignancies. Serial plasma samples from patients undergoing intended curative surgery for colorectal cancer were...... analyzed for complement factor C3 activation capacity. METHODS: Samples were collected from 91 patients with colorectal cancer and 13 with benign colorectal diseases before surgery and 1, 2, and 7 days after surgery, between 8 and 13 days after surgery, and 3, 6, 12, 18, 24, 36, 48, and 60 months after...

  10. The salivary scavenger and agglutinin (SALSA binds MBL and regulates the lectin pathway of complement in solution and on surfaces

    Directory of Open Access Journals (Sweden)

    Martin eParnov Reichhardt

    2012-07-01

    Full Text Available The scavenger receptor cysteine-rich (SRCR protein SALSA, also known as gp340, salivary agglutinin (SAG and deleted in malignant brain tumor 1 (DMBT1, is a 340 kDa glycoprotein expressed on mucosal surfaces and secreted into several body fluids. SALSA binds to a broad variety of microbes and endogenous ligands, such as complement factor C1q, surfactant proteins D and A (SP-D and SP-A and IgA. Our search for novel ligands of SALSA by direct protein-interaction studies led to the identification of mannan binding lectin (MBL as a new binding partner. We observed that surface-associated SALSA activates complement via binding of MBL. On the other hand, soluble SALSA was found to inhibit C. albicans-induced complement activation. Thus, SALSA has a dual complement regulatory function. It activates the lectin pathway when bound to a surface and inhibits it when free in the fluid-phase. These activities are mediated via a direct interaction with MBL.

  11. Distinct Polymer Architecture Mediates Switching of Complement Activation Pathways at the Nanosphere-Serum Interface: Implications for Stealth Nanoparticle Engineering

    DEFF Research Database (Denmark)

    Hamad, I.; Al-Hanbali, O.; Hunter, A.C.

    2010-01-01

    Nanoparticles with surface projected polyethyleneoxide (PEO) chains in 'mushroom-brush' and "brush" configurations display stealth properties in systemic circulation and have numerous applications in site specific targeting for controlled drug delivery and release as well as diagnostic Imaging. We...... reactions in some individuals Conformational states of surface chains, arising from the block copolymer poloxamine 908 adsorption, on polystyrene nanoparticles trigger complement activation differently. Alteration of copolymer architecture on nanospheres from mushroom to brush configuration not only....... Notably, the role properdin mediated activation of alternative pathway was only restricted to particles displaying PEO chains in a transition mushroom-brush configuration Since nanoparticle-mediated complement activation is of clinical concern our findings provide a rational basis for improved surface...

  12. Synthesis and classical pathway Complement inhibitory activity of C7-functionalized filifolinol derivatives, inspired in K-76 COOH.

    Science.gov (United States)

    Larghi, Enrique L; Operto, María A; Torres, Rene; Kaufman, Teodoro S

    2012-09-01

    A series of carboxylic acids carrying various functionalization on C-7 of their common 3H-spiro[benzofuran-2,1'-cyclohexane] skeleton were synthesized from filifolinol, as analogs of the natural Complement inhibitor K-76 COOH. In order to probe the relevance of the C-7 functionalization on their bioactivity, the ability of the analogs to inhibit Complement activation through the classical pathway was determined. The observed results suggest that functionalization of C-7 can modulate the inhibitory activity of the tested compounds. The 7-trifluoromethyl derivative was the compound with the lowest IC(50) value among the tested analogs (IC(50) = 100 μM), being more potent than K-76 COOH (IC(50) = 570 μM).

  13. Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain.

    Science.gov (United States)

    Shen, Y; Li, R; McGeer, E G; McGeer, P L

    1997-09-26

    To determine possible sources of complement proteins in the brain, we investigated by in situ hybridization expression of the mRNAs of C1q, C2, C3, C4, C5, C6, C7, C8 and C9 in postmortem Alzheimer disease (AD) and control brain tissue. We found detectable hybridization for all these components in the temporal cortex and hippocampus, with significantly higher levels being found in AD tissue. Hybridization signals were strongest over pyramidal neurons. Low or absent hybridization was seen in the visual cortex or cerebellum. These results suggest that the activated complement components found in association with AD lesions may be, in part, derived from neurons.

  14. Complement and the alternative pathway play an important role in LPS/D-GalN-induced fulminant hepatic failure.

    Directory of Open Access Journals (Sweden)

    Shihui Sun

    Full Text Available Fulminant hepatic failure (FHF is a clinically severe type of liver injury with an extremely high mortality rate. Although the pathological mechanisms of FHF are not well understood, evidence suggests that the complement system is involved in the pathogenesis of a variety of liver disorders. In the present study, to investigate the role of complement in FHF, we examined groups of mice following intraperitoneal injection of LPS/D-GalN: wild-type C57BL/6 mice, wild-type mice treated with a C3aR antagonist, C5aR monoclonal antibody (C5aRmAb or CR2-Factor H (CR2-fH, an inhibitor of the alternative pathway, and C3 deficient mice (C3⁻/⁻ mice. The animals were euthanized and samples analyzed at specific times after LPS/D-GalN injection. The results show that intraperitoneal administration of LPS/D-GalN activated the complement pathway, as evidenced by the hepatic deposition of C3 and C5b-9 and elevated serum levels of the complement activation product C3a, the level of which was associated with the severity of the liver damage. C3a receptor (C3aR and C5a receptor (C5aR expression was also upregulated. Compared with wild-type mice, C3⁻/⁻ mice survived significantly longer and displayed reduced liver inflammation and attenuated pathological damage following LPS/D-GalN injection. Similar levels of protection were seen in mice treated with C3aR antagonist,C5aRmAb or CR2-fH. These data indicate an important role for the C3a and C5a generated by the alternative pathway in LPS/D-GalN-induced FHF. The data further suggest that complement inhibition may be an effective strategy for the adjunctive treatment of fulminant hepatic failure.

  15. MBL2, FCN1, FCN2 and FCN3-The genes behind the initiation of the lectin pathway of complement

    DEFF Research Database (Denmark)

    Garred, Peter; Honoré, Christian; Ma, Ying Jie

    2009-01-01

    Mannose-binding lectin (MBL) and the ficolins (Ficolin-1, Ficolin-2 and Ficolin-3) are soluble collagen-like proteins that are involved in innate immune defence. They bind sugar structures or acetylated compounds present on microorganisms and on dying host cells and they initiate activation...... of the lectin complement pathway in varying degrees. Common variant alleles situated both in promoter and structural regions of the human MBL gene (MBL2) influence the stability and the serum concentration of the protein. Although not as thoroughly investigated as the MBL2 gene polymorphisms the ficolin genes...

  16. Deregulation of Interferon Signaling in Malignant Cells

    Directory of Open Access Journals (Sweden)

    Leonidas C. Platanias

    2010-02-01

    Full Text Available Interferons (IFNs are a family of cytokines with potent antiproliferative, antiviral, and immunomodulatory properties. Much has been learned about IFNs and IFN-activated signaling cascades over the last 50 years. Due to their potent antitumor effects in vitro and in vivo, recombinant IFNs have been used extensively over the years, alone or in combination with other drugs, for the treatment of various malignancies. This review summarizes the current knowledge on IFN signaling components and pathways that are deregulated in human malignancies. The relevance of deregulation of IFN signaling pathways in defective innate immune surveillance and tumorigenesis are discussed.

  17. Soluble Collectin-12 (CL-12) Is a Pattern Recognition Molecule Initiating Complement Activation via the Alternative Pathway.

    Science.gov (United States)

    Ma, Ying Jie; Hein, Estrid; Munthe-Fog, Lea; Skjoedt, Mikkel-Ole; Bayarri-Olmos, Rafael; Romani, Luigina; Garred, Peter

    2015-10-01

    Soluble defense collagens including the collectins play important roles in innate immunity. Recently, a new member of the collectin family named collectin-12 (CL-12 or CL-P1) has been identified. CL-12 is highly expressed in umbilical cord vascular endothelial cells as a transmembrane receptor and may recognize certain bacteria and fungi, leading to opsonophagocytosis. However, based on its structural and functional similarities with soluble collectins, we hypothesized the existence of a fluid-phase analog of CL-12 released from cells, which may function as a soluble pattern-recognition molecule. Using recombinant CL-12 full length or CL-12 extracellular domain, we determined the occurrence of soluble CL-12 shed from in vitro cultured cells. Western blot showed that soluble recombinant CL-12 migrated with a band corresponding to ∼ 120 kDa under reducing conditions, whereas under nonreducing conditions it presented multimeric assembly forms. Immunoprecipitation and Western blot analysis of human umbilical cord plasma enabled identification of a natural soluble form of CL-12 having an electrophoretic mobility pattern close to that of shed soluble recombinant CL-12. Soluble CL-12 could recognize Aspergillus fumigatus partially through the carbohydrate-recognition domain in a Ca(2+)-independent manner. This led to activation of the alternative pathway of complement exclusively via association with properdin on A. fumigatus as validated by detection of C3b deposition and formation of the terminal complement complex. These results demonstrate the existence of CL-12 in a soluble form and indicate a novel mechanism by which the alternative pathway of complement may be triggered directly by a soluble pattern-recognition molecule.

  18. Structural Basis for Eculizumab-Mediated Inhibition of the Complement Terminal Pathway

    DEFF Research Database (Denmark)

    Schatz-Jakobsen, Janus Asbjørn; zhang, yuchun; Johnson, Krista

    2016-01-01

    the proinflammatory metabolite C5a and formation of the membrane attack complex via C5b. Here we present the crystal structure of the complex between C5 and a Fab fragment with the same sequence as eculizumab at a resolution of 4.2 Å. Five complementarity determining regions (CDRs) contact the C5 MG7 domain, which......Eculizumab is a humanized monoclonal antibody approved for treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uraemic syndrome. Eculizumab binds complement component C5 and prevents its cleavage by C5 convertases, inhibiting release of both...... contains the entire epitope. A complete mutational scan of the sixty-six CDR residues identified twenty-eight residues as important for the C5-eculizumab interaction, and the structure of the complex offered an explanation for the reduced C5-binding observed for these mutant antibodies. Furthermore...

  19. Ficolins and the lectin pathway of complement in patients with systemic lupus erythematosus

    DEFF Research Database (Denmark)

    Hein, Estrid; Nielsen, Louise Aas; Nielsen, Christoffer T

    2015-01-01

    complement complex (TCC). SLE patients had increased levels of Ficolin-3, 21.6μg/ml as compared to 17.0μg/ml in healthy controls (P=0.0098). The Ficolin-1 plasma concentration was negatively correlated with SLE Disease Activity Index (SLEDAI) (Rho=-0.29, P=0.015) and positively correlated to the [Systemic...... Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index] (SDI) (Rho=0.27, P=0.026). The Ficolin-1 concentration was also associated with the occurrence of arterial (P=0.0053) but not venous thrombosis (P=0.42). Finally, deposition of C4, C3 and TCC...

  20. Ouabain rescues rat nephrogenesis during intrauterine growth restriction by regulating the complement and coagulation cascades and calcium signaling pathway.

    Science.gov (United States)

    Chen, L; Yue, J; Han, X; Li, J; Hu, Y

    2016-02-01

    Intrauterine growth restriction (IUGR) is associated with a reduction in the numbers of nephrons in neonates, which increases the risk of hypertension. Our previous study showed that ouabain protects the development of the embryonic kidney during IUGR. To explore this molecular mechanism, IUGR rats were induced by protein and calorie restriction throughout pregnancy, and ouabain was delivered using a mini osmotic pump. RNA sequencing technology was used to identify the differentially expressed genes (DEGs) of the embryonic kidneys. DEGs were submitted to the Database for Annotation and Visualization and Integrated Discovery, and gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted. Maternal malnutrition significantly reduced fetal weight, but ouabain treatment had no significant effect on body weight. A total of 322 (177 upregulated and 145 downregulated) DEGs were detected between control and the IUGR group. Meanwhile, 318 DEGs were found to be differentially expressed (180 increased and 138 decreased) between the IUGR group and the ouabain-treated group. KEGG pathway analysis indicated that maternal undernutrition mainly disrupts the complement and coagulation cascades and the calcium signaling pathway, which could be protected by ouabain treatment. Taken together, these two biological pathways may play an important role in nephrogenesis, indicating potential novel therapeutic targets against the unfavorable effects of IUGR.

  1. The down-stream effects of mannan-induced lectin complement pathway activation depend quantitatively on alternative pathway amplification

    DEFF Research Database (Denmark)

    Harboe, Morten; Garred, Peter; Karlstrøm, Ellen

    2009-01-01

    was not observed even at high mannan concentrations since addition of the inhibiting anti-MBL mAb 3F8 completely abolished generation of the terminal C5b-9 complex (TCC). However, selective blockade of AP by anti-factor D inhibited more than 80% of TCC release into the fluid phase after LP activation showing...... that AP amplification is quantitatively responsible for the final effect of initial specific LP activation. TCC generation on the solid phase was distinctly but less inhibited by anti-fD. C2 bypass of the LP pathway could be demonstrated, and AP amplification was also essential during C2 bypass in LP...... as shown by complete inhibition of TCC generation in C2-deficient serum by anti-fD and anti-properdin antibodies. In conclusion, the down-stream effect of LP activation depends strongly on AP amplification in normal human serum and in the C2 bypass pathway....

  2. Laboratory tests for disorders of complement and complement regulatory proteins.

    Science.gov (United States)

    Shih, Angela R; Murali, Mandakolathur R

    2015-12-01

    The complement pathway is a cascade of proteases that is involved in immune surveillance and innate immunity, as well as adaptive immunity. Dysfunction of the complement cascade may be mediated by aberrations in the pathways of activation, complement regulatory proteins, or complement deficiencies, and has been linked to a number of hematologic disorders, including paroxysmal noctural hemoglobinuria (PNH), hereditary angioedema (HAE), and atypical hemolytic-uremic syndrome (aHUS). Here, current laboratory tests for disorders of the complement pathway are reviewed, and their utility and limitations in hematologic disorders and systemic diseases are discussed. Current therapeutic advances targeting the complement pathway in treatment of complement-mediated hematologic disorders are also reviewed.

  3. Enzymatically Modified Low-Density Lipoprotein Is Recognized by C1q and Activates the Classical Complement Pathway

    Directory of Open Access Journals (Sweden)

    Gérard J. Arlaud

    2011-01-01

    Full Text Available Several studies suggest that the complement system is involved in atherogenesis. To further investigate this question, we have studied the ability of native and modified forms of LDL to bind and activate C1, the complex protease that triggers the classical pathway of complement. Unlike native LDL, oxidized (oxLDL and enzymatically modified (E-LDL derivatives were both recognized by the C1q subunit of C1, but only E-LDL particles, obtained by sequential treatment with a protease and then with cholesterol esterase, had the ability to trigger C1 activation. Further investigations revealed that C1q recognizes a lipid component of E-LDL. Several approaches, including reconstitution of model lipid vesicles, cosedimentation, and electron microscopy analyses, provided evidence that C1 binding to E-LDL particles is mediated by the C1q globular domain, which senses unesterified fatty acids generated by cholesterol esterase. The potential implications of these findings in atherogenesis are discussed.

  4. Deregulating Sunday Shop Policies

    NARCIS (Netherlands)

    Dijkgraaf, E.; Gradus, R.H.J.M.

    2006-01-01

    Sunday shop opening is deregulated to the municipal level in the Netherlands. Despite positive effects on economic growth and employment, many municipalities restrict Sunday shop opening. Based on 2003 data we show that diverse local characteristics, like the size of municipalities and religious and

  5. Deregulating Sunday Shop Policies

    NARCIS (Netherlands)

    E. Dijkgraaf (Elbert); R.H.J.M. Gradus (Raymond)

    2005-01-01

    textabstractSunday shop opening is deregulated to the municipal level in the Netherlands. Despite positive effects on economic growth and employment, many municipalities restrict Sunday shop opening. Based on 2003 data we show that diverse local characteristics, like the size of municipalities and r

  6. Regulation of the alternative pathway of complement modulates injury and immunity in a chronic model of dextran sulphate sodium-induced colitis

    Science.gov (United States)

    Elvington, M; Schepp-Berglind, J; Tomlinson, S

    2015-01-01

    The role of complement in inflammatory bowel disease (IBD) has been studied primarily using acute models, and it is unclear how complement affects processes in more relevant chronic models of IBD in which modulation of adaptive immunity and development of fibrosis have pathogenic roles. Using mice deficient in C1q/mannose-binding lectin (MBL) or C3, we demonstrated an important role for these opsonins and/or the classical pathway C3 convertase in providing protection against mucosal injury and infection in a model of chronic dextran sulphate sodium (DSS)-induced colitis. In contrast, deficiency of the alternative pathway (fB–/– mice) had significantly less impact on injury profiles. Consequently, the effect of a targeted inhibitor of the alternative pathway was investigated in a therapeutic protocol. Following the establishment of colitis, mice were treated with CR2-fH during subsequent periods of DSS treatment and acute injury (modelling relapse). CR2-fH significantly reduced complement activation, inflammation and injury in the colon, and additionally reduced fibrosis. Alternative pathway inhibition also altered the immune response in the chronic state in terms of reducing numbers of B cells, macrophages and mature dendritic cells in the lamina propria. This study indicates an important role for the alternative pathway of complement in the pathogenesis and the shaping of an immune response in chronic DSS-induced colitis, and supports further investigation into the use of targeted alternative pathway inhibition for the treatment of IBD. PMID:25293413

  7. Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water1

    Science.gov (United States)

    Muñoz, Alexandra; Chervona, Yana; Hall, Megan; Kluz, Thomas; Gamble, Mary V.; Costa, Max

    2015-01-01

    Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50–1000 µg/ L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p<0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic’s possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females. PMID:25759245

  8. Genetically engineered fusion of MAP-1 and factor H domains 1-5 generates a potent dual upstream inhibitor of both the lectin and alternative complement pathways.

    Science.gov (United States)

    Nordmaj, Mie Anemone; Munthe-Fog, Lea; Hein, Estrid; Skjoedt, Mikkel-Ole; Garred, Peter

    2015-12-01

    Inhibition of the complement cascade has emerged as an option for treatment of a range of diseases. Mannose-binding lectin/ficolin/collectin-associated protein (MAP-1) is a pattern recognition molecule (PRM)-associated inhibitor of the lectin pathway. The central regulator of the alternative pathway (AP) is complement factor H (FH). Our aim was to design a dual upstream inhibitor of both human lectin and APs by fusing MAP-1 with a part of FH. There were 2 different recombinant chimeric proteins comprising full-length human MAP-1 and the first 5 N-terminal domains of human FH designed. The FH domains were orientated either in the N- or C-terminal part of MAP-1. The complement inhibition potential in human serum was assessed. Both chimeric constructs displayed the characteristics of the native molecules and bound to the PRMs with an EC50 of ∼ 2 nM. However, when added to serum diluted 1:4 in a solid-phase functional assay, only the first 5 N-terminal domains of complement FH fused to the C-terminal part of full-length MAP-1 chimeric construct were able to combine inhibition of lectin and AP activation with an half maximal inhibitory concentration of ∼ 100 and 20 nM, respectively. No effect was seen on the classical pathway. Fusion of MAP-1 with FH domains represents a novel therapeutic approach for selective targeting upstream and central complement activation at sites of inflammation.

  9. A targeted inhibitor of the complement alternative pathway reduces RPE injury and angiogenesis in models of age-related macular degeneration.

    Science.gov (United States)

    Rohrer, Bärbel; Long, Qin; Coughlin, Beth; Renner, Brandon; Huang, Yuxiang; Kunchithapautham, Kannan; Ferreira, Viviana P; Pangburn, Michael K; Gilkeson, Gary S; Thurman, Joshua M; Tomlinson, Stephen; Holers, V Michael

    2010-01-01

    Genetic variations in complement factor H (fH), an inhibitor of the complement alternative pathway (CAP), and oxidative stress are associated with age-related macular degeneration (AMD). Recently, novel complement therapeutics have been created with the capacity to be "targeted" to sites of complement activation. One example is our recombinant form of fH, CR2-fH, which consists of the N-terminus of mouse fH that contains the CAP-inhibitory domain, linked to a complement receptor 2 (CR2) targeting fragment that binds complement activation products. CR2-fH was investigated in vivo in the mouse model of choroidal neovascularization (CNV) and in vitro in oxidatively stressed RPE cell monolayers. RPE deterioration and CNV development were found to require CAP activation, and specific CAP inhibition by CR2-fH reduced the loss of RPE integrity and angiogenesis in CNV. In both the in vivo and in vitro paradigm of RPE damage, a model requiring molecular events known to be involved in AMD, complement-dependent VEGF production, was confirmed. These data may open new avenues for AMD treatment strategies.

  10. Genome-wide pathway-based association study implicates complement system in the development of Kashin-Beck disease in Han Chinese.

    Science.gov (United States)

    Zhang, Feng; Wen, Yan; Guo, Xiong; Zhang, Yingang; Wang, Sen; Yang, Tielin; Shen, Hui; Chen, Xiangding; Tan, Lijun; Tian, Qing; Deng, Hong-Wen

    2015-02-01

    Kashin-Beck disease (KBD) is a chronic osteochondropathy. The pathogenesis of KBD remains unknown. To identify relevant biological pathways for KBD, we conducted a genome-wide pathway-based association study (GWPAS) following by replication analysis, totally using 2743 Chinese Han adults. A modified gene set enrichment algorithm was used to detect association between KBD and 963 biological pathways. Cartilage gene expression analysis and serum complement measurement were performed to evaluate the functional relevance of identified pathway with KBD. We found that the Complement and Coagulation Cascades (CACC) pathway was significantly associated with KBD (P value=3.09×10(-5), false-discovery rate=0.042). Within the CACC pathway, the most significant association was observed at rs1656966 (P value=1.97×10(-4)) of KNG1 gene. Further replication study observed that rs1656966 (P value=0.037) was significantly associated with KBD in an independent validation sample of 1026 subjects. Gene expression analysis observed that CFD (ratio=3.39±2.68), A2M (ratio=3.67±5.63), C5 (ratio=2.65±2.52) and CD46 (ratio=2.29±137) genes of the CACC pathway were up-regulated in KBD articular cartilage compared to healthy articular cartilage. The serum level of complement C5 in KBD patients were significantly higher than that in healthy controls (P value=0.038). Our study is the first to suggest that complement system-related CACC pathway contributed to the development of KBD.

  11. Association between lectin complement pathway initiators, C-reactive protein and left ventricular remodeling in myocardial infarction-a magnetic resonance study

    DEFF Research Database (Denmark)

    Schoos, Mikkel Malby; Munthe-Fog, Lea; Skjoedt, Mikkel-Ole;

    2013-01-01

    Lectin complement pathway (LP) activation is an important mechanism in myocardial ischemia reperfusion injury (IRI). LP is activated via the recognition molecules mannose-binding lectin (MBL), ficolins-2 and-3 and is regulated by MBL/Ficolin-associated Protein-1 (MAP-1). Also, C-reactive protein...

  12. Genetically engineered fusion of MAP-1 and factor H domains 1-5 generates a potent dual upstream inhibitor of both the lectin and alternative complement pathways

    DEFF Research Database (Denmark)

    Nordmaj, Mie Anemone; Munthe-Fog, Lea; Hein, Estrid

    2015-01-01

    Inhibition of the complement cascade has emerged as an option for treatment of a range of diseases. Mannose-binding lectin/ficolin/collectin-associated protein (MAP-1) is a pattern recognition molecule (PRM)-associated inhibitor of the lectin pathway. The central regulator of the alternative path...

  13. Complement activation by isolated myelin: activation of the classical pathway in the absence of myelin-specific antibodies.

    OpenAIRE

    Vanguri, P; Koski, C L; Silverman, B.; Shin, M L

    1982-01-01

    Many pathological conditions of the central nervous system involve damage to and removal of myelin membrane. Very little is known about initiation of this membrane damage and the mechanisms of disposal of the damaged tissue. We are interested in the interaction between complement (the components of complement are designated C1, C2, C3, etc.) and myelin membranes and the possible role of complement in amplifying myelin damage and in the disposal of damaged myelin in vivo, because activation of...

  14. Complement in autoimmune diseases.

    Science.gov (United States)

    Vignesh, Pandiarajan; Rawat, Amit; Sharma, Madhubala; Singh, Surjit

    2017-02-01

    The complement system is an ancient and evolutionary conserved element of the innate immune mechanism. It comprises of more than 20 serum proteins most of which are synthesized in the liver. These proteins are synthesized as inactive precursor proteins which are activated by appropriate stimuli. The activated forms of these proteins act as proteases and cleave other components successively in amplification pathways leading to exponential generation of final effectors. Three major pathways of complement pathways have been described, namely the classical, alternative and lectin pathways which are activated by different stimuli. However, all the 3 pathways converge on Complement C3. Cleavage of C3 and C5 successively leads to the production of the membrane attack complex which is final common effector. Excessive and uncontrolled activation of the complement has been implicated in the host of autoimmune diseases. But the complement has also been bemusedly described as the proverbial "double edged sword". On one hand, complement is the final effector of tissue injury in autoimmune diseases and on the other, deficiencies of some components of the complement can result in autoimmune diseases. Currently available tools such as enzyme based immunoassays for functional assessment of complement pathways, flow cytometry, next generation sequencing and proteomics-based approaches provide an exciting opportunity to study this ancient yet mysterious element of innate immunity.

  15. Complement system in zebrafish.

    Science.gov (United States)

    Zhang, Shicui; Cui, Pengfei

    2014-09-01

    Zebrafish is recently emerging as a model species for the study of immunology and human diseases. Complement system is the humoral backbone of the innate immune defense, and our knowledge as such in zebrafish has dramatically increased in the recent years. This review summarizes the current research progress of zebrafish complement system. The global searching for complement components in genome database, together with published data, has unveiled the existence of all the orthologues of mammalian complement components identified thus far, including the complement regulatory proteins and complement receptors, in zebrafish. Interestingly, zebrafish complement components also display some distinctive features, such as prominent levels of extrahepatic expression and isotypic diversity of the complement components. Future studies should focus on the following issues that would be of special importance for understanding the physiological role of complement components in zebrafish: conclusive identification of complement genes, especially those with isotypic diversity; analysis and elucidation of function and mechanism of complement components; modulation of innate and adaptive immune response by complement system; and unconventional roles of complement-triggered pathways.

  16. Complement activation pathways associated with islet cell surface antibody (ICSA derived from child patients with insulin-dependent diabetes mellitus (IDDM.

    Directory of Open Access Journals (Sweden)

    Okada,Soji

    1991-06-01

    Full Text Available We studied the pathways of complement activation associated with the islet cell surface antibody (ICSA obtained from sera of 7 patients (age less than 15 years with insulin dependent diabetes mellitus (IDDM. The target cells were 51CR labelled rat islet cells and the complement source was human AB serum. Complement-dependent antibody mediated cytotoxicity (CAMC activity was obtained using the percentage of cytotoxicity. CAMC activity of untreated sera was significantly inhibited by treating with EGTA or EDTA (p less than 0.001. The CAMC activity of EDTA-treated sera was significantly lower than that of EGTA-treated sera (p less than 0.001. In the inactivated human AB serum, it was lower than that of EGTA-treated sera (p less than 0.05, but not different from that of EDTA-treated sera. These results show that the complement activation associated with ICSA in patients occurred not only via the classical pathway but also via the alternative pathway.

  17. Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in mice

    Directory of Open Access Journals (Sweden)

    Holers V Michael

    2007-05-01

    Full Text Available Abstract Background The posttraumatic response to traumatic brain injury (TBI is characterized, in part, by activation of the innate immune response, including the complement system. We have recently shown that mice devoid of a functional alternative pathway of complement activation (factor B-/- mice are protected from complement-mediated neuroinflammation and neuropathology after TBI. In the present study, we extrapolated this knowledge from studies in genetically engineered mice to a pharmacological approach using a monoclonal anti-factor B antibody. This neutralizing antibody represents a specific and potent inhibitor of the alternative complement pathway in mice. Methods A focal trauma was applied to the left hemisphere of C57BL/6 mice (n = 89 using a standardized electric weight-drop model. Animals were randomly assigned to two treatment groups: (1 Systemic injection of 1 mg monoclonal anti-factor B antibody (mAb 1379 in 400 μl phosphate-buffered saline (PBS at 1 hour and 24 hours after trauma; (2 Systemic injection of vehicle only (400 μl PBS, as placebo control, at identical time-points after trauma. Sham-operated and untreated mice served as additional negative controls. Evaluation of neurological scores and analysis of brain tissue specimens and serum samples was performed at defined time-points for up to 1 week. Complement activation in serum was assessed by zymosan assay and by murine C5a ELISA. Brain samples were analyzed by immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL histochemistry, and real-time RT-PCR. Results The mAb 1379 leads to a significant inhibition of alternative pathway complement activity and to significantly attenuated C5a levels in serum, as compared to head-injured placebo-treated control mice. TBI induced histomorphological signs of neuroinflammation and neuronal apoptosis in the injured brain hemisphere of placebo-treated control mice for up to 7 days. In contrast, the

  18. The dual role of complement in the progression of renal disease in NZB/W F(1) mice and alternative pathway inhibition.

    Science.gov (United States)

    Sekine, Hideharu; Ruiz, Phillip; Gilkeson, Gary S; Tomlinson, Stephen

    2011-10-01

    Complement plays a dual role in the progression of systemic lupus erythematosus since it has important protective functions, such as the clearance of immune complexes and apoptotic cells, but is also a mediator of renal inflammation. To investigate this balance in a clinically relevant setting, we investigated how targeted inhibition of all complement pathways vs. targeted inhibition of only the alternative pathway impacts immune and therapeutic outcomes in NZB/W F(1) mice. Following onset of proteinuria, mice were injected twice weekly with CR2-fH (inhibits alternative pathway), CR2-Crry (inhibits all pathways at C3 activation step), sCR2 (C3d targeting vehicle) or saline. Sera were analyzed every 2 weeks for anti-dsDNA antibody levels, and urinary albumin excretion was determined. Kidneys were collected for histological evaluation at 32 weeks. Compared to the control group, all CR2-fH, CR2-Crry and sCR2 treated groups showed significantly reduced serum anti-dsDNA antibody levels and strong trends towards reduced glomerular IgG deposition levels. Glomerular C3 deposition levels were also significantly reduced in all three-treated groups. However, significant reductions of disease activity (albuminuria and glomerulonephritis) were only seen in the CR2-fH treated group. These data highlight the dual role played by complement in the pathogenesis of lupus, and demonstrate a benefit of selectively inhibiting the alternative complement pathway, presumably because of protective contributions from the classical and/or lectin pathways. The sCR2 targeting moiety appears to be contributing to therapeutic outcome via modulation of autoimmunity. Furthermore, these results are largely consistent with our previous data using the MRL/lpr lupus model, thus broadening the significance of these findings.

  19. Sundanese Complementation

    Science.gov (United States)

    Kurniawan, Eri

    2013-01-01

    The focus of this thesis is the description and analysis of clausal complementation in Sundanese, an Austronesian language spoken in Indonesia. The thesis examined a range of clausal complement types in Sundanese, which consists of (i) "yen/(wi)rehna" "that" complements, (ii) "pikeun" "for" complements,…

  20. Loss of DDB1 Leads to Transcriptional p53 Pathway Activation in Proliferating Cells, Cell Cycle Deregulation, and Apoptosis in Zebrafish Embryos

    Science.gov (United States)

    Hu, Zhilian; Holzschuh, Jochen; Driever, Wolfgang

    2015-01-01

    DNA damage-binding protein 1 (DDB1) is a large subunit of the heterodimeric DDB complex that recognizes DNA lesions and initiates the nucleotide excision repair process. DDB1 is also a component of the CUL4 E3 ligase complex involved in a broad spectrum of cellular processes by targeted ubiquitination of key regulators. Functions of DDB1 in development have been addressed in several model organisms, however, are not fully understood so far. Here we report an ENU induced mutant ddb1 allele (ddb1m863) identified in zebrafish (Danio rerio), and analyze its effects on development. Zebrafish ddb1 is expressed broadly, both maternally and zygotically, with enhanced expression in proliferation zones. The (ddb1m863 mutant allele affects the splice acceptor site of exon 20, causing a splicing defect that results in truncation of the 1140 amino acid protein after residue 800, lacking part of the β-propeller domain BPC and the C-terminal helical domain CTD. ddb1m863 zygotic mutant embryos have a pleiotropic phenotype, including smaller and abnormally shaped brain, head skeleton, eyes, jaw, and branchial arches, as well as reduced dopaminergic neuron groups. However, early forming tissues develop normally in zygotic ddb1m863 mutant embryos, which may be due to maternal rescue. In ddb1m863 mutant embryos, pcna-expressing proliferating cell populations were reduced, concurrent with increased apoptosis. We also observed a concomitant strong up-regulation of transcripts of the tumor suppressor p53 (tp53) and the cell cycle inhibitor cdkn1a (p21a/bCIP1/WAF1) in proliferating tissues. In addition, transcription of cyclin genes ccna2 and ccnd1 was deregulated in ddb1m863 mutants. Reduction of p53 activity by anti-sense morpholinos alleviated the apoptotic phenotype in ddb1m863 mutants. These results imply that Ddb1 may be involved in maintaining proper cell cycle progression and viability of dividing cells during development through transcriptional mechanisms regulating genes

  1. Heparin-coated cardiopulmonary bypass circuits selectively deplete the pattern recognition molecule ficolin-2 of the lectin complement pathway in vivo.

    Science.gov (United States)

    Hein, E; Munthe-Fog, L; Thiara, A S; Fiane, A E; Mollnes, T E; Garred, P

    2015-02-01

    The complement system can be activated via the lectin pathway by the recognition molecules mannose-binding lectin (MBL) and the ficolins. Ficolin-2 exhibits binding against a broad range of ligands, including biomaterials in vitro, and low ficolin-2 levels are associated with increased risk of infections. Thus, we investigated the biocompatibility of the recognition molecules of the lectin pathway in two different types of cardiopulmonary bypass circuits. Bloods were drawn at five time-points before, during and postoperatively from 30 patients undergoing elective cardiac surgery. Patients were randomized into two groups using different coatings of cardiopulmonary bypass circuits, Phisio® (phosphorylcholine polymer coating) and Bioline® (albumin-heparin coating). Concentrations of MBL, ficolin-1, -2 and -3 and soluble C3a and terminal complement complex (TCC) in plasma samples were measured. Ficolin-3-mediated complement activation potential was evaluated with C4, C3 and TCC as output. There was no significant difference between the two circuit materials regarding MBL, ficolin-1 and -3. In the Bioline® group the ficolin-2 levels decreased significantly after initiation of surgery (P circuits. Ficolin-3-mediated complement activation potential was reduced significantly in both groups after start of operation (P circuits and did not reach baseline level 24 h postoperation. These findings may have implications for the postoperative susceptibility to infections in patients undergoing extracorporeal circulation procedures.

  2. Multiple-response regression analysis links magnetic resonance imaging features to de-regulated protein expression and pathway activity in lower grade glioma.

    Science.gov (United States)

    Lehrer, Michael; Bhadra, Anindya; Ravikumar, Visweswaran; Chen, James Y; Wintermark, Max; Hwang, Scott N; Holder, Chad A; Huang, Erich P; Fevrier-Sullivan, Brenda; Freymann, John B; Rao, Arvind

    2017-05-01

    Lower grade gliomas (LGGs), lesions of WHO grades II and III, comprise 10-15% of primary brain tumors. In this first-of-a-kind study, we aim to carry out a radioproteomic characterization of LGGs using proteomics data from the TCGA and imaging data from the TCIA cohorts, to obtain an association between tumor MRI characteristics and protein measurements. The availability of linked imaging and molecular data permits the assessment of relationships between tumor genomic/proteomic measurements with phenotypic features. Multiple-response regression of the image-derived, radiologist scored features with reverse-phase protein array (RPPA) expression levels generated correlation coefficients for each combination of image-feature and protein or phospho-protein in the RPPA dataset. Significantly-associated proteins for VASARI features were analyzed with Ingenuity Pathway Analysis software. Hierarchical clustering of the results of the pathway analysis was used to determine which feature groups were most strongly correlated with pathway activity and cellular functions. The multiple-response regression approach identified multiple proteins associated with each VASARI imaging feature. VASARI features were found to be correlated with expression of IL8, PTEN, PI3K/Akt, Neuregulin, ERK/MAPK, p70S6K and EGF signaling pathways. Radioproteomics analysis might enable an insight into the phenotypic consequences of molecular aberrations in LGGs.

  3. Hippocampal Proteomic Analysis Reveals Distinct Pathway Deregulation Profiles at Early and Late Stages in a Rat Model of Alzheimer's-Like Amyloid Pathology.

    Science.gov (United States)

    Do Carmo, Sonia; Crynen, Gogce; Paradis, Tiffany; Reed, Jon; Iulita, M Florencia; Ducatenzeiler, Adriana; Crawford, Fiona; Cuello, A Claudio

    2017-05-13

    The cerebral accumulation and cytotoxicity of amyloid beta (Aβ) is central to Alzheimer's pathogenesis. However, little is known about how the amyloid pathology affects the global expression of brain proteins at different disease stages. In order to identify genotype and time-dependent significant changes in protein expression, we employed quantitative proteomics analysis of hippocampal tissue from the McGill-R-Thy1-APP rat model of Alzheimer-like amyloid pathology. McGill transgenic rats were compared to wild-type rats at early and late pathology stages, i.e., when intraneuronal Aβ amyloid burden is conspicuous and when extracellular amyloid plaques are abundant with more pronounced cognitive deficits. After correction for multiple testing, the expression levels of 64 proteins were found to be considerably different in transgenic versus wild-type rats at the pre-plaque stage (3 months), and 86 proteins in the post-plaque group (12 months), with only 9 differentially regulated proteins common to the 2 time-points. This minimal overlap supports the hypothesis that different molecular pathways are affected in the hippocampus at early and late stages of the amyloid pathology throughout its continuum. At early stages, disturbances in pathways related to cellular responses to stress, protein homeostasis, and neuronal structure are predominant, while disturbances in metabolic energy generation dominate at later stages. These results shed new light on the molecular pathways affected by the early accumulation of Aβ and how the evolving amyloid pathology impacts other complex metabolic pathways.

  4. Ataxia-telangiectasia group D complementing gene (ATDC promotes lung cancer cell proliferation by activating NF-κB pathway.

    Directory of Open Access Journals (Sweden)

    Zhong-Ping Tang

    Full Text Available Previous studies suggested Ataxia-telangiectasia group D complementing gene (ATDC as an oncogene in many types of cancer. However, its expression and biological functions in non-small cell lung cancer (NSCLC remain unclear. Herein, we investigated its expression pattern in 109 cases of human NSCLC samples by immunohistochemistry and found that ATDC was overexpressed in 62 of 109 NSCLC samples (56.88%. ATDC overexpression correlated with histological type (p<0.0001, tumor status (p = 0.0227 and histological differentiation (p = 0.0002. Next, we overexpressed ATDC in normal human bronchial epithelial cell line HBE and depleted its expression in NSCLC cell lines A549 and H1299. MTT and colony formation assay showed that ATDC overexpression promoted cell proliferation while its depletion inhibited cell growth. Furthermore, cell cycle analysis showed that ATDC overexpression decreased the percentage of cells in G1 phase and increased the percentage of cells in S phase, while ATDC siRNA treatment increased the G1 phase percentage and decreased the S phase percentage. Further study revealed that ATDC overexpression could up-regulate cyclin D1 and c-Myc expression in HBE cells while its depletion down-regulated cyclin D1 and c-Myc expression in A549 and H1299 cells. In addition, ATDC overexpression was also associated with an increased proliferation index, cyclin D1 and c-Myc expression in human NSCLC samples. Further experiments demonstrated that ATDC up-regulated cyclin D1 and c-Myc expression independent of wnt/β-catenin or p53 signaling pathway. Interestingly, ATDC overexpression increased NF-κB reporter luciferase activity and p-IκB protein level. Correspondingly, NF-κB inhibitor blocked the effect of ATDC on up-regulation of cyclin D1 and c-Myc. In conclusion, we demonstrated that ATDC could promote lung cancer proliferation through NF-κB induced up-regulation of cyclin D1 and c-Myc.

  5. Synergy between the classical and alternative pathways of complement is essential for conferring effective protection against the pandemic influenza A(H1N1) 2009 virus infection

    Science.gov (United States)

    Rattan, Ajitanuj; Pawar, Shailesh D.; Nawadkar, Renuka; Kulkarni, Neeraja

    2017-01-01

    The pandemic influenza A(H1N1) 2009 virus caused significant morbidity and mortality worldwide thus necessitating the need to understand the host factors that influence its control. Previously, the complement system has been shown to provide protection during the seasonal influenza virus infection, however, the role of individual complement pathways is not yet clear. Here, we have dissected the role of intact complement as well as of its individual activation pathways during the pandemic influenza virus infection using mouse strains deficient in various complement components. We show that the virus infection in C3-/- mice results in increased viral load and 100% mortality, which can be reversed by adoptive transfer of naïve wild-type (WT) splenocytes, purified splenic B cells, or passive transfer of immune sera from WT, but not C3-/- mice. Blocking of C3a and/or C5a receptor signaling in WT mice using receptor antagonists and use of C3aR-/- and C5aR-/- mice showed significant mortality after blocking/ablation of C3aR, with little or no effect after blocking/ablation of C5aR. Intriguingly, deficiency of C4 and FB in mice resulted in only partial mortality (24%-32%) suggesting a necessary cross-talk between the classical/lectin and alternative pathways for providing effective protection. In vitro virus neutralization experiments performed to probe the cross-talk between the various pathways indicated that activation of the classical and alternative pathways in concert, owing to coating of viral surface by antibodies, is needed for its efficient neutralization. Examination of the virus-specific complement-binding antibodies in virus positive subjects showed that their levels vary among individuals. Together these results indicate that cooperation between the classical and alternative pathways not only result in efficient direct neutralization of the pandemic influenza virus, but also lead to the optimum generation of C3a, which when sensed by the immune cells along

  6. The classical and alternative pathways of complement activation play distinct roles in spontaneous C3 fragment deposition and membrane attack complex (MAC) formation on human B lymphocytes

    DEFF Research Database (Denmark)

    Leslie, Robert Graham Quinton; Nielsen, Claus Henrik

    2004-01-01

    The contributions of the classical (CP) and alternative (AP) pathways of complement activation to the spontaneous deposition of C3 fragments and the formation of membrane attack complexes (MAC) on human B lymphocytes, were assessed by incubating peripheral blood mononuclear cells with autologous ...... of MAC formation was also found to be highly pathway dependent, with the AP being about 15-fold more efficient at initiating this process than the CP. A model accounting for the effectiveness of the AP in both preserving C3 fragment integrity and initiating MAC is presented....

  7. LMW-E/CDK2 deregulates acinar morphogenesis, induces tumorigenesis, and associates with the activated b-Raf-ERK1/2-mTOR pathway in breast cancer patients.

    Directory of Open Access Journals (Sweden)

    MyLinh T Duong

    Full Text Available Elastase-mediated cleavage of cyclin E generates low molecular weight cyclin E (LMW-E isoforms exhibiting enhanced CDK2-associated kinase activity and resistance to inhibition by CDK inhibitors p21 and p27. Approximately 27% of breast cancers express high LMW-E protein levels, which significantly correlates with poor survival. The objective of this study was to identify the signaling pathway(s deregulated by LMW-E expression in breast cancer patients and to identify pharmaceutical agents to effectively target this pathway. Ectopic LMW-E expression in nontumorigenic human mammary epithelial cells (hMECs was sufficient to generate xenografts with greater tumorigenic potential than full-length cyclin E, and the tumorigenicity was augmented by in vivo passaging. However, cyclin E mutants unable to interact with CDK2 protected hMECs from tumor development. When hMECs were cultured on Matrigel, LMW-E mediated aberrant acinar morphogenesis, including enlargement of acinar structures and formation of multi-acinar complexes, as denoted by reduced BIM and elevated Ki67 expression. Similarly, inducible expression of LMW-E in transgenic mice generated hyper-proliferative terminal end buds resulting in enhanced mammary tumor development. Reverse-phase protein array assay of 276 breast tumor patient samples and cells cultured on monolayer and in three-dimensional Matrigel demonstrated that, in terms of protein expression profile, hMECs cultured in Matrigel more closely resembled patient tissues than did cells cultured on monolayer. Additionally, the b-Raf-ERK1/2-mTOR pathway was activated in LMW-E-expressing patient samples, and activation of this pathway was associated with poor disease-specific survival. Combination treatment using roscovitine (CDK inhibitor plus either rapamycin (mTOR inhibitor or sorafenib (a pan kinase inhibitor targeting b-Raf effectively prevented aberrant acinar formation in LMW-E-expressing cells by inducing G1/S cell cycle arrest

  8. Chromatin deregulation in disease.

    Science.gov (United States)

    Mirabella, Anne C; Foster, Benjamin M; Bartke, Till

    2016-03-01

    The regulation of chromatin by epigenetic mechanisms plays a central role in gene expression and is essential for development and maintenance of cell identity and function. Aberrant chromatin regulation is observed in many diseases where it leads to defects in epigenetic gene regulation resulting in pathological gene expression programmes. These defects are caused by inherited or acquired mutations in genes encoding enzymes that deposit or remove DNA and histone modifications and that shape chromatin architecture. Chromatin deregulation often results in neurodevelopmental disorders and intellectual disabilities, frequently linked to physical and developmental abnormalities, but can also cause neurodegenerative diseases, immunodeficiency, or muscle wasting syndromes. Epigenetic diseases can either be of monogenic origin or manifest themselves as complex multifactorial diseases such as in congenital heart disease, autism spectrum disorders, or cancer in which mutations in chromatin regulators are contributing factors. The environment directly influences the epigenome and can induce changes that cause or predispose to diseases through risk factors such as stress, malnutrition or exposure to harmful chemicals. The plasticity of chromatin regulation makes targeting the enzymatic machinery an attractive strategy for therapeutic intervention and an increasing number of small molecule inhibitors against a variety of epigenetic regulators are in clinical use or under development. In this review, we will give an overview of the molecular lesions that underlie epigenetic diseases, and we will discuss the impact of the environment and prospects for epigenetic therapies.

  9. A meta-analysis of public microarray data identifies gene regulatory pathways deregulated in peripheral blood mononuclear cells from individuals with Systemic Lupus Erythematosus compared to those without.

    Science.gov (United States)

    Kröger, Wendy; Mapiye, Darlington; Entfellner, Jean-Baka Domelevo; Tiffin, Nicki

    2016-11-15

    Systemic Lupus Erythematosus (SLE) is a complex, multi-systemic, autoimmune disease for which the underlying aetiological mechanisms are poorly understood. The genetic and molecular processes underlying lupus have been extensively investigated using a variety of -omics approaches, including genome-wide association studies, candidate gene studies and microarray experiments of differential gene expression in lupus samples compared to controls. This study analyses a combination of existing microarray data sets to identify differentially regulated genetic pathways that are dysregulated in human peripheral blood mononuclear cells from SLE patients compared to unaffected controls. Two statistical approaches, quantile discretisation and scaling, are used to combine publicly available expression microarray datasets and perform a meta-analysis of differentially expressed genes. Differentially expressed genes implicated in interferon signaling were identified by the meta-analysis, in agreement with the findings of the individual studies that generated the datasets used. In contrast to the individual studies, however, the meta-analysis and subsequent pathway analysis additionally highlighted TLR signaling, oxidative phosphorylation and diapedesis and adhesion regulatory networks as being differentially regulated in peripheral blood mononuclear cells (PBMCs) from SLE patients compared to controls. Our analysis demonstrates that it is possible to derive additional information from publicly available expression data using meta-analysis techniques, which is particularly relevant to research into rare diseases where sample numbers can be limiting.

  10. A systematic analysis of the complement pathways in patients with neuromyelitis optica indicates alteration but no activation during remission

    DEFF Research Database (Denmark)

    Veszeli, Nóra; Füst, György; Csuka, Dorottya;

    2014-01-01

    Neuromyelitis optica (NMO) is an autoimmune demyelinating inflammatory disorder, mediated by pathogenic autoantibodies against aquaporin 4 (AQP4), the main water channel of the central nervous system (CNS). NMO is characterized by local IgG deposition and complement activation within the CNS...

  11. Cold activation of serum complement in patients with chronic hepatitis C: study on activating pathway and involvement of IgG.

    Directory of Open Access Journals (Sweden)

    Ishii Y

    2001-08-01

    Full Text Available It has been documented that the serum complement activities measured by hemolytic assay (CH50 are decreased after storage of sera at a low temperature in some patients with chronic hepatitis C. However, the mechanism of this phenomenon has not been identified yet. Here, we tried to elucidate factors involved in the cold activation of complement (CAC. To clarify what pathway is activated in CAC, we measured complement cleavage products after cold storage of sera. C4d increased significantly after 12 h-storage at cold temperatures in 5 CAC (+ sera compared with 5 CAC (- (P < 0.01 and 3 control sera (P < 0.05, while Bb did not increase in any of the groups. In order to determine whether IgG or IgG complex is necessary for CAC, 8 CAC (+ sera were incubated with Protein G Sepharose gel beads, and all of them retained hemolytic activities to some extent after cold storage. Column chromatography through Superose 6HR of CAC-positive serum identified the fractions containing molecules that induced CAC in normal serum, which were depleted by treatment with protein G Sepharose. In conclusion, CAC in hepatitis C seems to occur via a classical or lectin pathway, and the IgG complex produced in hepatitis C virus infection may be an important factor in inducing CAC, a common extrahepatic manifestation of hepatitis C.

  12. How companies fare through deregulation

    Energy Technology Data Exchange (ETDEWEB)

    Chwalowski, M.

    1977-01-01

    The electric utility industry must learn from past deregulation mistakes in order to develop successful corporate structures, services, and technologies that will succeed in a competitive environment. Failure to act will leave the average utility with less than a 50-50 chance of survival five years after deregulation commences. Most examinations of deregulation focus on its political aspects as well as its impacts on consumers, labor relations and safety. There are very few, if any, discussions about how companies themselves change. This article examines trends in the airline industry before and after deregulation. It concentrates on key indicators (e.g., internal structure, management team, employee profile, strategy, products and businesses, profitability) at discrete points in time. The conclusions point to general trends that characterized those transitions including the traits of successful companies.

  13. The extracellular adherence protein from Staphylococcus aureus inhibits the classical and lectin pathways of complement by blocking formation of the C3 proconvertase.

    Science.gov (United States)

    Woehl, Jordan L; Stapels, Daphne A C; Garcia, Brandon L; Ramyar, Kasra X; Keightley, Andrew; Ruyken, Maartje; Syriga, Maria; Sfyroera, Georgia; Weber, Alexander B; Zolkiewski, Michal; Ricklin, Daniel; Lambris, John D; Rooijakkers, Suzan H M; Geisbrecht, Brian V

    2014-12-15

    The pathogenic bacterium Staphylococcus aureus actively evades many aspects of human innate immunity by expressing a series of small inhibitory proteins. A number of these proteins inhibit the complement system, which labels bacteria for phagocytosis and generates inflammatory chemoattractants. Although the majority of staphylococcal complement inhibitors act on the alternative pathway to block the amplification loop, only a few proteins act on the initial recognition cascades that constitute the classical pathway (CP) and lectin pathway (LP). We screened a collection of recombinant, secreted staphylococcal proteins to determine whether S. aureus produces other molecules that inhibit the CP and/or LP. Using this approach, we identified the extracellular adherence protein (Eap) as a potent, specific inhibitor of both the CP and LP. We found that Eap blocked CP/LP-dependent activation of C3, but not C4, and that Eap likewise inhibited deposition of C3b on the surface of S. aureus cells. In turn, this significantly diminished the extent of S. aureus opsonophagocytosis and killing by neutrophils. This combination of functional properties suggested that Eap acts specifically at the level of the CP/LP C3 convertase (C4b2a). Indeed, we demonstrated a direct, nanomolar-affinity interaction of Eap with C4b. Eap binding to C4b inhibited binding of both full-length C2 and its C2b fragment, which indicated that Eap disrupts formation of the CP/LP C3 proconvertase (C4b2). As a whole, our results demonstrate that S. aureus inhibits two initiation routes of complement by expression of the Eap protein, and thereby define a novel mechanism of immune evasion.

  14. Regulatory components of the alternative complement pathway in endothelial cell cytoplasm, factor H and factor I, are not packaged in Weibel-Palade bodies.

    Directory of Open Access Journals (Sweden)

    Nancy A Turner

    Full Text Available It was recently reported that factor H, a regulatory component of the alternative complement pathway, is stored with von Willebrand factor (VWF in the Weibel-Palade bodies of endothelial cells. If this were to be the case, it would have therapeutic importance for patients with the atypical hemolytic-uremic syndrome that can be caused either by a heterozygous defect in the factor H gene or by the presence of an autoantibody against factor H. The in vivo Weibel-Palade body secretagogue, des-amino-D-arginine vasopressin (DDAVP, would be expected to increase transiently the circulating factor H levels, in addition to increasing the circulating levels of VWF. We describe experiments demonstrating that factor H is released from endothelial cell cytoplasm without a secondary storage site. These experiments showed that factor H is not stored with VWF in endothelial cell Weibel-Palade bodies, and is not secreted in response in vitro in response to the Weibel-Palade body secretagogue, histamine. Furthermore, the in vivo Weibel-Palade body secretagogue, DDAVP does not increase the circulating factor H levels concomitantly with DDAVP-induced increased VWF. Factor I, a regulatory component of the alternative complement pathway that is functionally related to factor H, is also located in endothelial cell cytoplasm, and is also not present in endothelial cell Weibel-Palade bodies. Our data demonstrate that the factor H and factor I regulatory proteins of the alternative complement pathway are not stored in Weibel-Palade bodies. DDAVP induces the secretion into human plasma of VWF--but not factor H.

  15. Regulatory components of the alternative complement pathway in endothelial cell cytoplasm, factor H and factor I, are not packaged in Weibel-Palade bodies.

    Science.gov (United States)

    Turner, Nancy A; Sartain, Sarah E; Hui, Shiu-Ki; Moake, Joel L

    2015-01-01

    It was recently reported that factor H, a regulatory component of the alternative complement pathway, is stored with von Willebrand factor (VWF) in the Weibel-Palade bodies of endothelial cells. If this were to be the case, it would have therapeutic importance for patients with the atypical hemolytic-uremic syndrome that can be caused either by a heterozygous defect in the factor H gene or by the presence of an autoantibody against factor H. The in vivo Weibel-Palade body secretagogue, des-amino-D-arginine vasopressin (DDAVP), would be expected to increase transiently the circulating factor H levels, in addition to increasing the circulating levels of VWF. We describe experiments demonstrating that factor H is released from endothelial cell cytoplasm without a secondary storage site. These experiments showed that factor H is not stored with VWF in endothelial cell Weibel-Palade bodies, and is not secreted in response in vitro in response to the Weibel-Palade body secretagogue, histamine. Furthermore, the in vivo Weibel-Palade body secretagogue, DDAVP does not increase the circulating factor H levels concomitantly with DDAVP-induced increased VWF. Factor I, a regulatory component of the alternative complement pathway that is functionally related to factor H, is also located in endothelial cell cytoplasm, and is also not present in endothelial cell Weibel-Palade bodies. Our data demonstrate that the factor H and factor I regulatory proteins of the alternative complement pathway are not stored in Weibel-Palade bodies. DDAVP induces the secretion into human plasma of VWF--but not factor H.

  16. Complement in hemolytic anemia.

    Science.gov (United States)

    Brodsky, Robert A

    2015-01-01

    Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. For optimal therapy, it is critical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopenic purpura; however, novel bioassays are being developed. In cold agglutinin disease (CAD), immunoglobulin M autoantibodies fix complement on the surface of red cells, resulting in extravascular hemolysis by the reticuloendothelial system. Drugs that inhibit complement activation are increasingly being used to treat these diseases. This article discusses the pathophysiology, diagnosis, and therapy for PNH, aHUS, and CAD.

  17. Material properties in complement activation

    DEFF Research Database (Denmark)

    Moghimi, S. Moein; Andersen, Alina Joukainen; Ahmadvand, Davoud

    2011-01-01

    -immune performance’ relationship studies in nanomedicine research at many fronts. The interaction between nanomaterials and the complement system is complex and regulated by inter-related factors that include nanoscale size, morphology and surface characteristics. Each of these parameters may affect complement...... activation differently and through different sensing molecules and initiation pathways. The importance of material properties in triggering complement is considered and mechanistic aspects discussed. Mechanistic understanding of complement events could provide rational approaches for improved material design...

  18. Meningococcal surface fibril (Msf) binds to activated vitronectin and inhibits the terminal complement pathway to increase serum resistance.

    Science.gov (United States)

    Griffiths, Natalie J; Hill, Darryl J; Borodina, Elena; Sessions, Richard B; Devos, Nathalie I; Feron, Christiane M; Poolman, Jan T; Virji, Mumtaz

    2011-12-01

    Complement evasion is an important survival strategy of Neisseria meningitidis (Nm) during colonization and infection. Previously, we have shown that Nm Opc binds to serum vitronectin to inhibit complement-mediated killing. In this study, we demonstrate meningococcal interactions with vitronectin via a novel adhesin, Msf (meningococcal surface fibril, previously NhhA or Hsf). As with Opc, Msf binds preferentially to activated vitronectin (aVn), engaging at its N-terminal region but the C-terminal heparin binding domain may also participate. However, unlike Opc, the latter binding is not heparin-mediated. By binding to aVn, Msf or Opc can impart serum resistance, which is further increased in coexpressers, a phenomenon dependent on serum aVn concentrations. The survival fitness of aVn-binding derivatives was evident from mixed population studies, in which msf/opc mutants were preferentially depleted. In addition, using vitronectin peptides to block Msf-aVn interactions, aVn-induced inhibition of lytic C5b-9 formation and of serum killing could be reversed. As Msf-encoding gene is ubiquitous in the meningococcal strains examined and is expressed in vivo, serum resistance via Msf may be of significance to meningococcal pathogenesis. The data imply that vitronectin binding may be an important strategy for the in vivo survival of Nm for which the bacterium has evolved redundant mechanisms.

  19. Gene array analysis of a rat model of liver transplant tolerance identifies increased complement C3 and the STAT-1/IRF-1 pathway during tolerance induction.

    Science.gov (United States)

    Cordoba, Shaun P; Wang, Chuanmin; Williams, Rohan; Li, Jian; Smit, Lynn; Sharland, Alexandra; Allen, Richard; McCaughan, Geoffrey; Bishop, Alex

    2006-04-01

    This study aimed to define the molecular mechanism during induction of spontaneous liver transplant tolerance using microarrays and to focus on molecular pathways associated with tolerance by meta-analysis with published studies. The differences in the early immune response between PVG to DA liver transplant recipients that are spontaneously tolerant (TOL) and PVG to Lewis liver transplants that reject (REJ) were examined. Spleens from TOL and REJ on days 1 and 3 were compared by 2 color microarray. Forty-six of 199 genes differentially expressed between TOL and REJ had an immunological function. More immune genes were increased in TOL vs. REJ on day 1, including STAT-1, IRF-1 and complement C3. Differential expression of selected genes was confirmed by quantitative RT-PCR. The results were compared to two published high-throughput studies of rat liver transplant tolerance and showed that C3 was increased in all three models, while STAT-1 and IRF-1 were increased in two models. The early increases in immune genes in TOL confirmed previous reports of an active early immune response in TOL. In conclusion, the increase in STAT-1, IRF-1 and complement component C3 in several models of liver transplant tolerance suggests that the STAT-1/IRF-1 apoptotic pathway and C3 may be involved in the tolerogenic mechanism.

  20. Hepatitis C Virus-Induced Upregulation of MicroRNA miR-146a-5p in Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis.

    Science.gov (United States)

    Bandiera, Simonetta; Pernot, Sophie; El Saghire, Hussein; Durand, Sarah C; Thumann, Christine; Crouchet, Emilie; Ye, Tao; Fofana, Isabel; Oudot, Marine A; Barths, Jochen; Schuster, Catherine; Pessaux, Patrick; Heim, Markus H; Baumert, Thomas F; Zeisel, Mirjam B

    2016-07-15

    Hepatitis C virus (HCV)-induced chronic liver disease is a leading cause of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying HCC development following chronic HCV infection remain poorly understood. MicroRNAs (miRNAs) play an important role in homeostasis within the liver, and deregulation of miRNAs has been associated with liver disease, including HCC. While host miRNAs are essential for HCV replication, viral infection in turn appears to induce alterations of intrahepatic miRNA networks. Although the cross talk between HCV and liver cell miRNAs most likely contributes to liver disease pathogenesis, the functional involvement of miRNAs in HCV-driven hepatocyte injury and HCC remains elusive. Here we combined a hepatocyte-like cell-based model system, high-throughput small RNA sequencing, computational analysis, and functional studies to investigate HCV-miRNA interactions that may contribute to liver disease and HCC. Profiling analyses indicated that HCV infection differentially regulated the expression of 72 miRNAs by at least 2-fold, including miRNAs that were previously described to target genes associated with inflammation, fibrosis, and cancer development. Further investigation demonstrated that the miR-146a-5p level was consistently increased in HCV-infected hepatocyte-like cells and primary human hepatocytes, as well as in liver tissue from HCV-infected patients. Genome-wide microarray and computational analyses indicated that miR-146a-5p overexpression modulates pathways that are related to liver disease and HCC development. Furthermore, we showed that miR-146a-5p has a positive impact on late steps of the viral replication cycle, thereby increasing HCV infection. Collectively, our data indicate that the HCV-induced increase in miR-146a-5p expression both promotes viral infection and is relevant for pathogenesis of liver disease. HCV is a leading cause of chronic liver disease and cancer. However, how HCV induces liver cancer

  1. Substituting complements

    OpenAIRE

    Dari-Mattiacci, G.; Parisi, F.; Heller, M.

    2009-01-01

    The presence of multiple sellers in the provision of (nonsubstitutable) complementary goods leads to outcomes that are worse than those generated by a monopoly (with a vertically integrated production of complements), a problem known in the economic literature as complementary oligopoly and recently popularized in the legal literature as the tragedy of the anticommons. We ask the following question: how many substitutes for each complement are necessary to render the presence of multiple sell...

  2. Role of complement in glomerular diseases.

    Science.gov (United States)

    Mao, Song; Zhang, Jianhua

    2016-01-01

    The complement system, composed of nearly 30 proteins, is a key regulator of immunity. The complement system is critical for protecting hosts from invading pathogens. Dysregulation of this system is associated with susceptibility to infection and various autoimmune diseases. Furthermore, complement activation due to the defective regulation of the alternative pathway will induce glomerular diseases. Anti-complement therapy has been applied in various glomerular diseases. Signaling pathways might be very important in the pathogenesis of glomerular diseases. This review will give a relatively complete signaling pathway flowchart for complement and a comprehensive understanding of the underlying role of complement in glomerular diseases.

  3. Leishmania spp: Delta-aminolevulinate-inducible neogenesis of porphyria by genetic complementation of incomplete heme biosynthesis pathway

    Science.gov (United States)

    Dutta, Sujoy; Furuyama, Kazumichi; Sassa, Shigeru; Chang, Kwang-Poo Chang

    2008-01-01

    To further develop the Leishmania model for porphyria based on their deficiencies in heme biosynthesis, three Old World species were doubly transfected as before for Leishmania amazonensis with cDNAs, encoding the 2nd and 3rd enzymes in the pathway. Expression of the transgenes was verified immunologically at the protein level and functionally by uroporphyrin neogenesis that occurs only after exposure of the double-transfectants to delta-aminolevulinate. All species examined were equally deficient in heme biosynthesis, as indicated by the accumulation of uroporphyrin as the sole porphyrin and the production of coproporphyrin upon further transfection of one representative species with the downstream gene. The results obtained thus demonstrate that at least the first five enzymes for heme biosynthesis are absent in all species examined, rendering their transfectants inducible with aminolevulinate to accumulate porphyrins and thus useful as cellular models for human porphyrias. PMID:18164705

  4. Deregulator: Judgment Day for microeconomics

    Energy Technology Data Exchange (ETDEWEB)

    Keen, S. [University of Western Sydney, Penrith (Australia). School of Economics and Finance

    2004-09-01

    The economic theory that motivated the deregulation and privatization of the US electricity industry is seriously flawed in three crucial ways. First, the Marshallian theory of the firm is based on two mathematical errors which, when amended, reverse the accepted welfare rankings of competitive and monopoly industry structures: on the grounds of corrected neoclassical theory, monopoly should be preferred to competition. Second, while proponents of deregulation expected market-clearing equilibrium prices to apply, it is well known that the equilibrium of a system of spot market prices is unstable. This implies that imposing spot market pricing on as basic an industry as electricity is likely to lead to the kind of volatility observed under the deregulation. Third, extensive empirical research has established that on the order of 95% of firms do not produce under conditions of rising marginal cost. Requiring electricity firms to price at marginal cost was therefore likely to lead to bankruptcies, as indeed occurred. The economic preference for marginal cost spot market pricing is therefore theoretically unsound, and it is no wonder that the actual deregulatory experience was as bad as it was. (author)

  5. Substituting complements

    NARCIS (Netherlands)

    G. Dari-Mattiacci; F. Parisi

    2006-01-01

    The presence of multiple sellers in the provision of (nonsubstitutable) complementary goods leads to outcomes that are worse than those generated by a monopoly (with a vertically integrated production of complements), a problem known in the economic literature as complementary oligopoly and recently

  6. Substituting complements

    NARCIS (Netherlands)

    G. Dari-Mattiacci; F. Parisi

    2009-01-01

    The presence of multiple sellers in the provision of (nonsubstitutable) complementary goods leads to outcomes that are worse than those generated by a monopoly (with a vertically integrated production of complements), a problem known in the economic literature as complementary oligopoly and recently

  7. Microglia, Alzheimer's Disease, and Complement

    Directory of Open Access Journals (Sweden)

    Helen Crehan

    2012-01-01

    Full Text Available Microglia, the immune cell of the brain, are implicated in cascades leading to neuronal loss and cognitive decline in Alzheimer’s disease (AD. Recent genome-wide association studies have indicated a number of risk factors for the development of late-onset AD. Two of these risk factors are an altered immune response and polymorphisms in complement receptor 1. In view of these findings, we discuss how complement signalling in the AD brain and microglial responses in AD intersect. Dysregulation of the complement cascade, either by changes in receptor expression, enhanced activation of different complement pathways or imbalances between complement factor production and complement cascade inhibitors may all contribute to the involvement of complement in AD. Altered complement signalling may reduce the ability of microglia to phagocytose apoptotic cells and clear amyloid beta peptides, modulate the expression by microglia of complement components and receptors, promote complement factor production by plaque-associated cytokines derived from activated microglia and astrocytes, and disrupt complement inhibitor production. The evidence presented here indicates that microglia in AD are influenced by complement factors to adopt protective or harmful phenotypes and the challenge ahead lies in understanding how this can be manipulated to therapeutic advantage to treat late onset AD.

  8. Mouse Ficolin B Has an Ability to Form Complexes with Mannose-Binding Lectin-Associated Serine Proteases and Activate Complement through the Lectin Pathway

    Directory of Open Access Journals (Sweden)

    Yuichi Endo

    2012-01-01

    Full Text Available Ficolins are thought to be pathogen-associated-molecular-pattern-(PAMP- recognition molecules that function to support innate immunity. Like mannose-binding lectins (MBLs, most mammalian ficolins form complexes with MBL-associated serine proteases (MASPs, leading to complement activation via the lectin pathway. However, the ability of murine ficolin B, a homologue of human M-ficolin, to perform this function is still controversial. The results of the present study show that ficolin B in mouse bone marrow is an oligomeric protein. Ficolin B, pulled down using GlcNAc-agarose, contained very low, but detectable, amounts of MASP-2 and small MBL-associated protein (sMAP and showed detectable C4-deposition activity on immobilized N-acetylglucosamine. These biochemical features of ficolin B were confirmed using recombinant mouse ficolin B produced in CHO cells. Taken together, these results suggest that like other mammalian homologues, murine ficolin B has an ability to exert its function via the lectin pathway.

  9. Thrombotic Microangiopathy Care Pathway: A Consensus Statement for the Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group.

    Science.gov (United States)

    Go, Ronald S; Winters, Jeffrey L; Leung, Nelson; Murray, David L; Willrich, Maria A; Abraham, Roshini S; Amer, Hatem; Hogan, William J; Marshall, Ariela L; Sethi, Sanjeev; Tran, Cheryl L; Chen, Dong; Pruthi, Rajiv K; Ashrani, Aneel A; Fervenza, Fernando C; Cramer, Carl H; Rodriguez, Vilmarie; Wolanskyj, Alexandra P; Thomé, Stephan D; Hook, C Christopher

    2016-09-01

    Thrombotic microangiopathies (TMAs) comprise a heterogeneous set of conditions linked by a common histopathologic finding of endothelial damage resulting in microvascular thromboses and potentially serious complications. The typical clinical presentation is microangiopathic hemolytic anemia accompanied by thrombocytopenia with varying degrees of organ ischemia. The differential diagnoses are generally broad, while the workup is frequently complex and can be confusing. This statement represents the joint recommendations from a multidisciplinary team of Mayo Clinic physicians specializing in the management of TMA. It comprises a series of evidence- and consensus-based clinical pathways developed to allow a uniform approach to the spectrum of care including when to suspect TMA, what differential diagnoses to consider, which diagnostic tests to order, and how to provide initial empiric therapy, as well as some guidance on subsequent management. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  10. Complement Evasion by Pathogenic Leptospira.

    Science.gov (United States)

    Fraga, Tatiana Rodrigues; Isaac, Lourdes; Barbosa, Angela Silva

    2016-01-01

    Leptospirosis is a neglected infectious disease caused by spirochetes from the genus Leptospira. Pathogenic microorganisms, notably those which reach the blood circulation such as Leptospira, have evolved multiple strategies to escape the host complement system, which is important for innate and acquired immunity. Leptospira avoid complement-mediated killing through: (i) recruitment of host complement regulators; (ii) acquisition of host proteases that cleave complement proteins on the bacterial surface; and, (iii) secretion of proteases that inactivate complement proteins in the Leptospira surroundings. The recruitment of host soluble complement regulatory proteins includes the acquisition of Factor H (FH) and FH-like-1 (alternative pathway), C4b-binding protein (C4BP) (classical and lectin pathways), and vitronectin (Vn) (terminal pathway). Once bound to the leptospiral surface, FH and C4BP retain cofactor activity of Factor I in the cleavage of C3b and C4b, respectively. Vn acquisition by leptospires may result in terminal pathway inhibition by blocking C9 polymerization. The second evasion mechanism lies in plasminogen (PLG) binding to the leptospiral surface. In the presence of host activators, PLG is converted to enzymatically active plasmin, which is able to degrade C3b, C4b, and C5 at the surface of the pathogen. A third strategy used by leptospires to escape from complement system is the active secretion of proteases. Pathogenic, but not saprophytic leptospires, are able to secrete metalloproteases that cleave C3 (central complement molecule), Factor B (alternative pathway), and C4 and C2 (classical and lectin pathways). The purpose of this review is to fully explore these complement evasion mechanisms, which act together to favor Leptospira survival and multiplication in the host.

  11. Inflation targeting and product market deregulation

    OpenAIRE

    Moretti, Laura

    2012-01-01

    I evaluate the effect of inflation targeting on inflation and how it interacts with product market deregulation during the disinflationary process in the 1990s. Using a sample of 21 OECD countries, I show that, after controlling for product market deregulation, the effect of inflation targeting is quantitatively important and statistically significant. Moreover, product market deregulation also matters in particular in countries that adopted an inflation targeting regime. I propose a New Keyn...

  12. Early graft failure of GalTKO pig organs in baboons is reduced by expression of a human complement pathway-regulatory protein.

    Science.gov (United States)

    Azimzadeh, Agnes M; Kelishadi, Sean S; Ezzelarab, Mohamed B; Singh, Avneesh K; Stoddard, Tiffany; Iwase, Hayato; Zhang, Tianshu; Burdorf, Lars; Sievert, Evelyn; Avon, Chris; Cheng, Xiangfei; Ayares, David; Horvath, Keith A; Corcoran, Philip C; Mohiuddin, Muhammad M; Barth, Rolf N; Cooper, David K C; Pierson, Richard N

    2015-01-01

    We describe the incidence of early graft failure (EGF, defined as loss of function from any cause within 3 days after transplant) in a large cohort of GalTKO pig organs transplanted into baboons in three centers, and the effect of additional expression of a human complement pathway-regulatory protein, CD46 or CD55 (GalTKO.hCPRP). Baboon recipients of life-supporting GalTKO kidney (n = 7) or heterotopic heart (n = 14) grafts received either no immunosuppression (n = 4), or one of several partial or full immunosuppressive regimens (n = 17). Fourteen additional baboons received a GalTKO.hCPRP kidney (n = 5) or heart (n = 9) and similar treatment regimens. Immunologic, pathologic, and coagulation parameters were measured at frequent intervals. EGF of GalTKO organs occurred in 9/21 baboons (43%). hCPRP expression reduced the GalTKO EGF incidence to 7% (1/14; P organs in which EGF developed (P organ failure, and (iii) the expression of a hCPRP reduces EGF but does not prevent systemic coagulation activation. Additional strategies will be required to control coagulation activation.

  13. Entamoeba histolytica and E. dispar Calreticulin: Inhibition of Classical Complement Pathway and Differences in the Level of Expression in Amoebic Liver Abscess

    Directory of Open Access Journals (Sweden)

    Cecilia Ximénez

    2014-01-01

    Full Text Available The role of calreticulin (CRT in host-parasite interactions has recently become an important area of research. Information about the functions of calreticulin and its relevance to the physiology of Entamoeba parasites is limited. The present work demonstrates that CRT of both pathogenic E. histolytica and nonpathogenic E. dispar species specifically interacted with human C1q inhibiting the activation of the classical complement pathway. Using recombinant EhCRT protein, we demonstrate that CRT interaction site and human C1q is located at the N-terminal region of EhCRT. The immunofluorescence and confocal microscopy experiments show that CRT and human C1q colocalize in the cytoplasmic vesicles and near to the surface membrane of previously permeabilized trophozoites or are incubated with normal human serum which is known to destroy trophozoites. In the presence of peripheral mononuclear blood cells, the distribution of EhCRT and C1q is clearly over the surface membrane of trophozoites. Nevertheless, the level of expression of CRT in situ in lesions of amoebic liver abscess (ALA in the hamster model is different in both Entamoeba species; this molecule is expressed in higher levels in E. histolytica than in E. dispar. This result suggests that EhCRT may modulate some functions during the early moments of the host-parasite relationship.

  14. Review on complement analysis method and the roles of glycosaminoglycans in the complement system.

    Science.gov (United States)

    Li, Lian; Li, Yan; Ijaz, Muhammad; Shahbaz, Muhammad; Lian, Qianqian; Wang, Fengshan

    2015-12-10

    Complement system is composed of over 30 proteins and it plays important roles in self-defence and inflammation. There are three activation pathways, including classical pathway, alternative pathway and lectin pathway, in complement system, and they are associated with many diseases such as osteoarthritis and age-related macular degeneration. Modulation of the complement system may be a promising strategy in the treatment of related diseases. Glycosaminoglycans are anionic linear polysaccharides without branches. They are one kind of multi-functional macromolecules which have great potential in regulating complement system. This review is organized around two aspects between the introduction of complement system and the interaction of glycosaminoglycans with complement system. Three complement activation pathways and the biological significance were introduced first. Then functional analysis methods were compared to provide a strategy for potential glycosaminoglycans screen. Finally, the roles of glycosaminoglycans played in the complement system were summed up.

  15. Evolution of the complement system.

    Science.gov (United States)

    Nonaka, Masaru

    2014-01-01

    The mammalian complement system constitutes a highly sophisticated body defense machinery comprising more than 30 components. Research into the evolutionary origin of the complement system has identified a primitive version composed of the central component C3 and two activation proteases Bf and MASP in cnidaria. This suggests that the complement system was established in the common ancestor of eumetazoa more than 500 million years ago. The original activation mechanism of the original complement system is believed to be close to the mammalian lectin and alternative activation pathways, and its main role seems to be opsonization and induction of inflammation. This primitive complement system has been retained by most deuterostomes without major change until the appearance of jawed vertebrates. At this stage, duplication of the C3, Bf and MASP genes as well as recruitment of membrane attack components added the classical and lytic pathways to the primitive complement system, converting it to the modern complement system. In contrast, the complement system was lost multiple times independently in the protostome lineage.

  16. Economic and Environmental Effects of Airline Deregulation

    NARCIS (Netherlands)

    Schipper, Youdi; Rietveld, Piet

    1997-01-01

    This paper deals with the issue of regulatory reform in the airline industry, in connection with environmental externalities. Deregulation has led to shorter routes, higher frequencies, probably larger aircraft sizes and more intense peak traffic at airports. In addition, deregulation has led to low

  17. China Gradually Deregulates Aviation Fuels Market

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    @@ China will gradually deregulate the aviation fuels market to allow the oil and petrochemical enterprises to become shareholders of China Aviation Fuels Corporation (CAFC) so that the aviation fuels suppliers can operate at a lower cost. Deregulation of the air fuels market aims at reduction of aviation fuels price to spur development of China's air transportation industry.

  18. Economic and Environmental Effects of Airline Deregulation

    NARCIS (Netherlands)

    Schipper, Youdi; Rietveld, Piet

    1997-01-01

    This paper deals with the issue of regulatory reform in the airline industry, in connection with environmental externalities. Deregulation has led to shorter routes, higher frequencies, probably larger aircraft sizes and more intense peak traffic at airports. In addition, deregulation has led to

  19. BF*F allotype of the alternative pathway of complement: A marker of protection against the development of antiphospholipid antibodies in patients with systemic lupus erythematosus.

    Science.gov (United States)

    Picceli, V F; Skare, T L; Nisihara, R M; Nass, F R; Messias-Reason, I T; Utiyama, S R R

    2016-04-01

    B factor (BF) from the alternative complement pathway seems to participate in the pathophysiology of systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). To study the allotypic variability of BF in SLE and their associations with clinical and autoantibodies profile. BF allotypes were determined by high-voltage agarose gel electrophoresis, under constant cooling, followed by immunofixation with anti-human BF antibody, in 188 SLE patients and 103 controls. Clinical and serological data were obtained from medical examination and records. No significant differences of BF variants between patients and controls were found, neither in relation to epidemiologic or clinical manifestations. Associations of phenotype BF SS07 and allotype BF*S07 were found with anticardiolipin IgM (aCl-IgM) antibodies (p = 0.014 and p = 0.009 respectively), but not with aCl-IgG, lupus anticoagulant (LA), anti β2GPI or clinical APS. A significant decrease in BF*F allotype (p = 0.043) and BF SF phenotype (p = 0.018) was detected in patients with anti-phospholipid antibodies as a whole (aCl-IgG, aCl-IgM, LA and anti β2GPI). There is a link between phenotype BF SS07 and allotype BF*S07 with aCl-IgM in SLE patients; BF*F allotype could be considered a marker of protection against the development of antiphospholipid antibodies in these patients. © The Author(s) 2015.

  20. The complement system in human cardiometabolic disease.

    Science.gov (United States)

    Hertle, E; Stehouwer, C D A; van Greevenbroek, M M J

    2014-10-01

    The complement system has been implicated in obesity, fatty liver, diabetes and cardiovascular disease (CVD). Complement factors are produced in adipose tissue and appear to be involved in adipose tissue metabolism and local inflammation. Thereby complement links adipose tissue inflammation to systemic metabolic derangements, such as low-grade inflammation, insulin resistance and dyslipidaemia. Furthermore, complement has been implicated in pathophysiological mechanisms of diet- and alcohol induced liver damage, hyperglycaemia, endothelial dysfunction, atherosclerosis and fibrinolysis. In this review, we summarize current evidence on the role of the complement system in several processes of human cardiometabolic disease. C3 is the central component in complement activation, and has most widely been studied in humans. C3 concentrations are associated with insulin resistance, liver dysfunction, risk of the metabolic syndrome, type 2 diabetes and CVD. C3 can be activated by the classical, the lectin and the alternative pathway of complement activation; and downstream activation of C3 activates the terminal pathway. Complement may also be activated via extrinsic proteases of the coagulation, fibrinolysis and the kinin systems. Studies on the different complement activation pathways in human cardiometabolic disease are limited, but available evidence suggests that they may have distinct roles in processes underlying cardiometabolic disease. The lectin pathway appeared beneficial in some studies on type 2 diabetes and CVD, while factors of the classical and the alternative pathway were related to unfavourable cardiometabolic traits. The terminal complement pathway was also implicated in insulin resistance and liver disease, and appears to have a prominent role in acute and advanced CVD. The available human data suggest a complex and potentially causal role for the complement system in human cardiometabolic disease. Further, preferably longitudinal studies are needed to

  1. Studies of the binding of ficolin-2 and ficolin-3 from the complement lectin pathway to Leptospira biflexa, Pasteurella pneumotropica and Diarrheagenic Escherichia coli

    DEFF Research Database (Denmark)

    Sahagún-Ruiz, Alfredo; Breda, Leandro Carvalho Dantas; Valencia, Mónica Marcela Castiblanco

    2015-01-01

    ficolins, ficolin-2 and ficolin-3 with different Gram-negative bacteria. We used recombinant ficolin molecules and normal human serum, which were detected with anti-ficolin monoclonal antibodies. In addition we investigated the capacity of these pathogens to activate the lectin pathway of complement system......, enteropathogenic Escherichia coli (EPEC) serotype O111ab:H2 and enteroaggregative E. coli (EAEC) serogroup O71 but not four enterohemorrhagic E. coli, three EPEC, three EAEC and two nonpathogenic E. coli strains (DH5α and HB101). The lectin pathway was activated by Pasteurella pneumotropica, EPEC O111ab:H2...

  2. Exchange Rate Deregulation and Industrial Performance: An ...

    African Journals Online (AJOL)

    FIRST LADY

    Key Words: Exchange Rate, Deregulation, Industrial Performance, Co- integration ... and exchange risk there from. In fact ... factors underscore the importance of exchange rate to the economic well being of ..... Wearing. Apparel, Footwear,.

  3. Deregulated microRNAs in myotonic dystrophy type 2.

    Directory of Open Access Journals (Sweden)

    Simona Greco

    Full Text Available Myotonic Dystrophy Type-2 (DM2 is an autosomal dominant disease caused by the expansion of a CCTG tetraplet repeat. It is a multisystemic disorder, affecting skeletal muscles, the heart, the eye, the central nervous system and the endocrine system. Since microRNA (miRNA expression is disrupted in Myotonic Dystrophy Type-1 and many other myopathies, miRNAs deregulation was studied in skeletal muscle biopsies of 13 DM2 patients and 13 controls. Eleven miRNAs were deregulated: 9 displayed higher levels compared to controls (miR-34a-5p, miR-34b-3p, miR-34c-5p, miR-146b-5p, miR-208a, miR-221-3p and miR-381, while 4 were decreased (miR-125b-5p, miR-193a-3p, miR-193b-3p and miR-378a-3p. To explore the relevance of DM2 miRNA deregulation, the predicted interactions between miRNA and mRNA were investigated. Global gene expression was analyzed in DM2 and controls and bioinformatic analysis identified more than 1,000 miRNA/mRNA interactions. Pathway and function analysis highlighted the involvement of the miRNA-deregulated mRNAs in multiple aspects of DM2 pathophysiology. In conclusion, the observed miRNA dysregulations may contribute to DM2 pathogenetic mechanisms.

  4. Banking deregulation and corporate tax avoidance

    Directory of Open Access Journals (Sweden)

    Bill B. Francis

    2017-06-01

    Full Text Available We investigate whether tax avoidance substitutes for external financing. We exploit interstate banking deregulation as a quasi-external shock to examine whether firms engage in less tax avoidance after banking deregulation, because of cheaper and easier access to credit from banks. We find no empirical evidence to support this substitutive relation, even for firms with higher financial constraints or firms with higher external financing dependence.

  5. Transmission planning in a deregulated environment

    OpenAIRE

    Xu, Zhao

    2006-01-01

    The worldwide trend for the deregulation of the electricity generation and transmission industries has led to dramatic changes in system operation and planning procedures. The optimum approach to transmission-expansion planning in a deregulated environment is an open problem especially when the responsibilities of the organisations carrying out the planning work need to be addressed. To date there is a consensus that the system operator and network manager perform the expansion planning work ...

  6. Heparin-coated cardiopulmonary bypass circuits selectively deplete the pattern recognition molecule ficolin-2 of the lectin complement pathway in vivo

    DEFF Research Database (Denmark)

    Hein, Estrid; Munthe-Fog, L; Thiara, A S

    2015-01-01

    randomized into two groups using different coatings of cardiopulmonary bypass circuits, Phisio® (phosphorylcholine polymer coating) and Bioline® (albumin-heparin coating). Concentrations of MBL, ficolin-1, -2 and -3 and soluble C3a and terminal complement complex (TCC) in plasma samples were measured....... Ficolin-3-mediated complement activation potential was evaluated with C4, C3 and TCC as output. There was no significant difference between the two circuit materials regarding MBL, ficolin-1 and -3. In the Bioline® group the ficolin-2 levels decreased significantly after initiation of surgery (P ....0001) and remained reduced throughout the sampling period. This was not seen for Phisio®-coated circuits. Ficolin-3-mediated complement activation potential was reduced significantly in both groups after start of operation (P TCC in the samples were increased (P

  7. The outer membrane protease PgtE of Salmonella enterica interferes with the alternative complement pathway by cleaving factors B and H

    OpenAIRE

    Rauna eRiva; Korhonen, Timo K.; Seppo eMeri

    2015-01-01

    The virulence factor PgtE is an outer membrane protease (omptin) of the zoonotic pathogen Salmonella enterica that causes diseases ranging from gastroenteritis to severe enteric fever. It is surface exposed in bacteria that have a short-chain, i.e., rough LPS, as observed e.g., in bacteria residing inside macrophages or just emerging from them. We investigated whether PgtE cleaves the complement factors B (B) and H (H), key proteins controlling formation and inactivation of the complement pro...

  8. Complement: an overview for the clinician.

    Science.gov (United States)

    Varela, Juan Carlos; Tomlinson, Stephen

    2015-06-01

    The complement system is an essential component of the immune system. It is a highly integrative system and has a number of functions, including host defense, removal of injured cells and debris, modulation of metabolic and regenerative processes, and regulation of adaptive immunity. Complement is activated via different pathways and it is regulated tightly by several mechanisms to prevent host injury. Imbalance between complement activation and regulation can manifest in disease and injury to self. This article provides an outline of complement activation pathways, regulatory mechanisms, and normal physiologic functions of the system.

  9. Design and development of TT30, a novel C3d-targeted C3/C5 convertase inhibitor for treatment of human complement alternative pathway-mediated diseases.

    Science.gov (United States)

    Fridkis-Hareli, Masha; Storek, Michael; Mazsaroff, Istvan; Risitano, Antonio M; Lundberg, Ante S; Horvath, Christopher J; Holers, V Michael

    2011-10-27

    To selectively modulate human complement alternative pathway (CAP) activity implicated in a wide range of acute and chronic inflammatory conditions and to provide local cell surface and tissue-based inhibition of complement-induced damage, we developed TT30, a novel therapeutic fusion protein linking the human complement receptor type 2 (CR2/CD21) C3 fragment (C3frag = iC3b, C3dg, C3d)-binding domain with the CAP inhibitory domain of human factor H (fH). TT30 efficiently blocks ex vivo CAP-dependent C3frag accumulation on activated surfaces, membrane attack complex (MAC) formation and hemolysis of RBCs in a CR2-dependent manner, and with a ∼ 150-fold potency gain over fH, without interference of C3 activation or MAC formation through the classic and lectin pathways. TT30 protects RBCs from hemolysis and remains bound and detectable for at least 24 hours. TT30 selectively inhibits CAP in cynomolgus monkeys and is bioavailable after subcutaneous injection. Using a unique combination of targeting and effector domains, TT30 controls cell surface CAP activation and has substantial potential utility for the treatment of human CAP-mediated diseases.

  10. The outer membrane protease PgtE of Salmonella enterica interferes with the alternative complement pathway by cleaving factors B and H

    Directory of Open Access Journals (Sweden)

    Rauna eRiva

    2015-02-01

    Full Text Available The virulence factor PgtE is an outer membrane protease (omptin of the zoonotic pathogen Salmonella enterica that causes diseases ranging from gastroenteritis to severe enteric fever. It is surface exposed in bacteria that have a short-chain, i.e. rough LPS, as observed e.g. in bacteria residing inside macrophages or just emerging from them. We investigated whether PgtE cleaves the complement factors B (B and H (H, key proteins controlling formation and inactivation of the complement protein C3b and thereby the activity of the complement system. S. enterica serovar Typhimurium or omptin-expressing recombinant E. coli bacteria were incubated with purified human complement proteins or recombinant H fragments. PgtE cleaved both B and H, whereas its close homolog Pla of Yersinia pestis cleaved only H. H was cleaved at both N- and C-termini, while the central region resisted proteolysis. Because of multiple effects of PgtE on complement components (cleavage of C3, C3b, B and H we assessed its effect on the opsonophagocytosis of Salmonella. In human serum, C3 cleavage was dependent on proteolytically active PgtE. Human neutrophils interacted less with serum-opsonized FITC-stained S. enterica 14028R than with the isogenic ΔpgtE strain, as analyzed by flow cytometry. In conclusion, cleavage of B and H by PgtE, together with C3 cleavage, affects the C3-mediated recognition of S. enterica by human neutrophils, thus thwarting the immune protection against Salmonella.

  11. The complement system and adverse pregnancy outcomes.

    Science.gov (United States)

    Regal, Jean F; Gilbert, Jeffrey S; Burwick, Richard M

    2015-09-01

    Adverse pregnancy outcomes significantly contribute to morbidity and mortality for mother and child, with lifelong health consequences for both. The innate and adaptive immune system must be regulated to insure survival of the fetal allograft, and the complement system is no exception. An intact complement system optimizes placental development and function and is essential to maintain host defense and fetal survival. Complement regulation is apparent at the placental interface from early pregnancy with some degree of complement activation occurring normally throughout gestation. However, a number of pregnancy complications including early pregnancy loss, fetal growth restriction, hypertensive disorders of pregnancy and preterm birth are associated with excessive or misdirected complement activation, and are more frequent in women with inherited or acquired complement system disorders or complement gene mutations. Clinical studies employing complement biomarkers in plasma and urine implicate dysregulated complement activation in components of each of the adverse pregnancy outcomes. In addition, mechanistic studies in rat and mouse models of adverse pregnancy outcomes address the complement pathways or activation products of importance and allow critical analysis of the pathophysiology. Targeted complement therapeutics are already in use to control adverse pregnancy outcomes in select situations. A clearer understanding of the role of the complement system in both normal pregnancy and complicated or failed pregnancy will allow a rational approach to future therapeutic strategies for manipulating complement with the goal of mitigating adverse pregnancy outcomes, preserving host defense, and improving long term outcomes for both mother and child.

  12. Deregulation upon DNA damage revealed by joint analysis of context-specific perturbation data

    Directory of Open Access Journals (Sweden)

    Biecek Przemysław

    2011-06-01

    Full Text Available Abstract Background Deregulation between two different cell populations manifests itself in changing gene expression patterns and changing regulatory interactions. Accumulating knowledge about biological networks creates an opportunity to study these changes in their cellular context. Results We analyze re-wiring of regulatory networks based on cell population-specific perturbation data and knowledge about signaling pathways and their target genes. We quantify deregulation by merging regulatory signal from the two cell populations into one score. This joint approach, called JODA, proves advantageous over separate analysis of the cell populations and analysis without incorporation of knowledge. JODA is implemented and freely available in a Bioconductor package 'joda'. Conclusions Using JODA, we show wide-spread re-wiring of gene regulatory networks upon neocarzinostatin-induced DNA damage in Human cells. We recover 645 deregulated genes in thirteen functional clusters performing the rich program of response to damage. We find that the clusters contain many previously characterized neocarzinostatin target genes. We investigate connectivity between those genes, explaining their cooperation in performing the common functions. We review genes with the most extreme deregulation scores, reporting their involvement in response to DNA damage. Finally, we investigate the indirect impact of the ATM pathway on the deregulated genes, and build a hypothetical hierarchy of direct regulation. These results prove that JODA is a step forward to a systems level, mechanistic understanding of changes in gene regulation between different cell populations.

  13. Complement in Lupus Nephritis: New Perspectives

    Science.gov (United States)

    Bao, Lihua; Cunningham, Patrick N.; Quigg, Richard J.

    2015-01-01

    Background Systemic lupus erythematosus (SLE) is an autoimmune disorder caused by loss of tolerance to self-antigens, the production of autoantibodies and deposition of complement-fixing immune complexes (ICs) in injured tissues. SLE is characterized by a wide range of clinical manifestations and targeted organs, with lupus nephritis being one of the most serious complications. The complement system consists of three pathways and is tightly controlled by a set of regulatory proteins to prevent injudicious complement activation on host tissue. The involvement of the complement system in the pathogenesis of SLE is well accepted; yet, its exact role is still not clear. Summary Complement plays dual roles in the pathogenesis of SLE. On the one hand, the complement system appears to have protective features in that hereditary homozygous deficiencies of classical pathway components, such as C1q and C4, are associated with an increased risk for SLE. On the other hand, IC-mediated activation of complement in affected tissues is clearly evident in both experimental and human SLE along with pathological features that are logical consequences of complement activation. Studies in genetically altered mice have shown that lack of complement inhibitors, such as complement factor H (CFH) or decay-accelerating factor (DAF) accelerates the development of experimental lupus nephritis, while treatment with recombinant protein inhibitors, such as Crry-Ig, CR2-Crry, CR2-DAF and CR2-CFH, ameliorates the disease development. Complement-targeted drugs, including soluble complement receptor 1 (TP10), C1 esterase inhibitor and a monoclonal anti-C5 antibody (eculizumab), have been shown to inhibit complement safely, and are now being investigated in a variety of clinical conditions. Key Messages SLE is an autoimmune disorder which targets multiple systems. Complement is centrally involved and plays dual roles in the pathogenesis of SLE. Studies from experimental lupus models and clinical

  14. Deregulated tyrosine-phenylalanine metabolism in pulmonary tuberculosis patients.

    Science.gov (United States)

    Das, Mrinal Kumar; Bishwal, Subasa Chandra; Das, Aleena; Dabral, Deepti; Badireddy, Vinod Kumar; Pandit, Bhaswati; Varghese, George M; Nanda, Ranjan Kumar

    2015-04-01

    Metabolic profiling of biofluids from tuberculosis (TB) patients would help us in understanding the disease pathophysiology and may also be useful for the development of novel diagnostics and host-directed therapy. In this pilot study we have compared the urine metabolic profiles of two groups of subjects having similar TB symptoms and categorized as active TB (ATB, n = 21) and non-TB (NTB, n = 21) based on GeneXpert test results. Silylation, gas chromatography mass spectrometry, and standard chemometric methods were employed to identify the important molecules and deregulated metabolic pathways. Eleven active TB patients were followed up on longitudinally for comparative urine metabolic profiling with healthy controls (n = 11). A set of 42 features qualified to have a variable importance parameter score of > 1.5 of a partial least-squares discriminate analysis model and fold change of > 1.5 at p value phenylalanine metabolic pathway. In the longitudinal study we observed a treatment-dependent trend in the urine metabolome of follow-up samples, and subjects declared as clinically cured showed similar metabolic profile as those of asymptomatic healthy subjects. The deregulated tyrosine-phenylalanine axis reveals a potential target for diagnostics and intervention in TB.

  15. Transmission planning in a deregulated environment

    DEFF Research Database (Denmark)

    Xu, Zhao

    2006-01-01

    The worldwide trend for the deregulation of the electricity generation and transmission industries has led to dramatic changes in system operation and planning procedures. The optimum approach to transmission-expansion planning in a deregulated environment is an open problem especially when...... the responsibilities of the organisations carrying out the planning work need to be addressed. To date there is a consensus that the system operator and network manager perform the expansion planning work in a centralised way. However, with an increasing input from the electricity market, the objectives, constraints...... and approaches toward transmission planning should be carefully designed to ensure system reliability as well as meeting the market requirements. A market-oriented approach for transmission planning in a deregulated environment is proposed. Case studies using the IEEE 14-bus system and the Australian national...

  16. Protein engineering to target complement evasion in cancer.

    Science.gov (United States)

    Carter, Darrick; Lieber, André

    2014-01-21

    The complement system is composed of soluble factors in plasma that enhance or "complement" immune-mediated killing through innate and adaptive mechanisms. Activation of complement causes recruitment of immune cells; opsonization of coated cells; and direct killing of affected cells through a membrane attack complex (MAC). Tumor cells up-regulate complement inhibitory factors - one of several strategies to evade the immune system. In many cases as the tumor progresses, dramatic increases in complement inhibitory factors are found on these cells. This review focuses on the classic complement pathway and the role of major complement inhibitory factors in cancer immune evasion as well as on how current protein engineering efforts are being employed to increase complement fixing or to reverse complement resistance leading to better therapeutic outcomes in oncology. Strategies discussed include engineering of antibodies to enhance complement fixation, antibodies that neutralize complement inhibitory proteins as well as engineered constructs that specifically target inhibition of the complement system.

  17. Genetic, molecular and functional analyses of complement factor I deficiency

    DEFF Research Database (Denmark)

    Nilsson, S.C.; Trouw, L.A.; Renault, N.;

    2009-01-01

    Complete deficiency of complement inhibitor factor I (FI) results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation leading to susceptibility to infections. Current genetic examination of two patients with near complete FI deficiency and three...

  18. Ras-mediated deregulation of the circadian clock in cancer.

    Directory of Open Access Journals (Sweden)

    Angela Relógio

    Full Text Available Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock.

  19. Deregulation-restructuring: Evidence for individual industries

    Energy Technology Data Exchange (ETDEWEB)

    Costello, K.W.; Graniere, R.J.

    1997-05-01

    Several studies have measured the effects of regulation on a particular industry. These studies range widely in sophistication, from simple observation (comparison) of pre-transformation and post-transformation actual industry performance to econometric analysis that attempt to separate the effects of deregulation from other factors in explaining changes in an industry`s performance. The major problem with observation studies is that they are unable to measure the effect of one particular event, such as deregulation, on an industry`s performance. For example, at the same time that the United Kingdom privatized its electric power industry, it also radically restructured the industry to encourage competition and instituted a price-cap mechanism to regulate the prices of transmission, distribution, and bundled retail services. Subsequent to these changes in 1991, real prices for most UK electricity customers have fallen. It is not certain however, which of these factors was most important or even contributed to the decline in price. In any event, one must be cautious in interpreting the results of studies that attempt to measure the effect of deregulation per se for a specific industry. This report highlights major outcomes for five industries undergoing deregulation or major regulatory and restructuring reforms. These include the natural gas, transportation, UK electric power, financial, and telecommunications industries. Particular attention was given to the historical development of events in the telecommunications industry.

  20. Molecular Mechanisms of p53 Deregulation in Cancer: An Overview in Multiple Myeloma.

    Science.gov (United States)

    Herrero, Ana B; Rojas, Elizabeta A; Misiewicz-Krzeminska, Irena; Krzeminski, Patryk; Gutiérrez, Norma C

    2016-11-30

    The p53 pathway is inactivated in the majority of human cancers. Although this perturbation frequently occurs through the mutation or deletion of p53 itself, there are other mechanisms that can attenuate the pathway and contribute to tumorigenesis. For example, overexpression of important p53 negative regulators, such as murine double minute 2 (MDM2) or murine double minute 4 (MDM4), epigenetic deregulation, or even alterations in TP53 mRNA splicing. In this work, we will review the different mechanisms of p53 pathway inhibition in cancer with special focus on multiple myeloma (MM), the second most common hematological malignancy, with low incidence of p53 mutations/deletions but growing evidence of indirect p53 pathway deregulation. Translational implications for MM and cancer prognosis and treatment are also reviewed.

  1. Shear stress-mediated changes in the expression of complement regulatory protein CD59 on human endothelial progenitor cells by ECM-integrinαVβ3-F-actin pathway in vitro.

    Science.gov (United States)

    Cui, Xiaodong; Zhang, Xiaoyun; Bu, Hongnan; Liu, Na; Li, Hong; Guan, Xiumei; Yan, Hong; Wang, Yuzhen; Zhang, Hua; Ding, Yuzhen; Cheng, Min

    2017-09-21

    Membrane regulatory proteins, such as CD46, CD55, and CD59, prevent excess complement activation and to protect cells from damage. Previous investigations confirmed that shear stress in the physiological range was more favorable for endothelial progenitor cells (EPCs) to repair injured vascular endothelial cells and operates mainly in atheroprotective actions. However, detailed events that contribute to shear stress-induced protection in EPCs, particularly the mechanisms of signal transduction, remain poorly understood. In this study, we observed shear stress-mediated changes in the expression of complement regulatory proteins CD46, CD55, and CD59 on human EPCs and focused on the mechanical transmission mechanism in transformed cells in response to the ECM-F-actin pathway in vitro. Shear stress was observed to promote the expression of complement regulatory protein CD59, but not CD46 or CD55, on EPCs. In addition, the shear stress-induced CD59 expression was confirmed to be associated with the ECM components and was alleviated in EPCs pretreated with GRGDSP, which inhibits ECM components-integrin interaction. Furthermore, shear stress also promotes the rearrangement and polymerization of F-actin. However, shear stress-induced CD59 expression was reduced when the F-actin stress fiber formation process was delayed by Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) or destroyed by cytochalasin D (Cyto D), while Jasplakinolide (JAS) reversed the expression of CD59 through promotion of F-actin polymerization and its stabilizing capacities. Our results indicates that shear stress is an important mediator in EPC expression of CD59 regulated by the ECM-F-actin pathway, which is a key factor in preventing membrane attack complex (MAC) -mediated cell autolysis. Copyright © 2017. Published by Elsevier Inc.

  2. The complement system in systemic autoimmune disease.

    Science.gov (United States)

    Chen, Min; Daha, Mohamed R; Kallenberg, Cees G M

    2010-05-01

    Complement is part of the innate immune system. Its major function is recognition and elimination of pathogens via direct killing and/or stimulation of phagocytosis. Activation of the complement system is, however, also involved in the pathogenesis of the systemic autoimmune diseases. Activation via the classical pathway has long been recognized in immune complex-mediated diseases such as cryoglobulinemic vasculitis and systemic lupus erythematosus (SLE). In SLE, the role of complement is somewhat paradoxical. It is involved in autoantibody-initiated tissue damage on the one hand, but, on the other hand, it appears to have protective features as hereditary deficiencies of classical pathway components are associated with an increased risk for SLE. There is increasing evidence that the alternative pathway of complement, even more than the classical pathway, is involved in many systemic autoimmune diseases. This is true for IgA-dominant Henoch Schönlein Purpura, in which additional activation of the lectin pathway contributes to more severe disease. In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis the complement system was considered not to be involved since immunoglobulin deposition is generally absent in the lesions. However, recent studies, both in human and animal models, demonstrated complement activation via the alternative pathway as a major pathogenic mechanism. Insight into the role of the various pathways of complement in the systemic autoimmune diseases including the vasculitides opens up new ways of treatment by blocking effector pathways of complement. This has been demonstrated for monoclonal antibodies to C5 or C5a in experimental anti-phospholipid antibody syndrome and ANCA-associated vasculitis.

  3. Alzheimer's beta-amyloid peptides can activate the early components of complement classical pathway in a C1q-independent manner.

    Science.gov (United States)

    Bergamaschini, L; Canziani, S; Bottasso, B; Cugno, M; Braidotti, P; Agostoni, A

    1999-03-01

    beta-Amyloid (beta-A) accumulates in the brain of patients with Alzheimer's disease (AD) and is presumably involved in the pathogenesis of this disease, on account of its neurotoxicity and complement-activating ability. Although assembly of beta-A in particular aggregates seems to be crucial, soluble non-fibrillar beta-A may also be involved. Non-fibrillar beta-A does not bind C1q, so we investigated alternative mechanisms of beta-A-dependent complement activation in vitro. On incubation with normal human plasma, non-fibrillar beta-A 1-42, and truncated peptide 1-28, induced dose-dependent activation of C1s and C4, sparing C3, as assessed by densitometric analysis of immunostained membrane after SDS-PAGE and Western blotting. The mechanism of C4 activation was not dependent on C1q, because non-fibrillar beta-A can still activate C1s and C4 in plasma genetically deficient in C1q (C1qd). In Factor XII-deficient plasma (F.XIId) the amount of cleaved C4 was about 5-10% less that in C1qd and in normal EDTA plasma; the reconstitution of F.XIId plasma with physiologic concentrations of F.XII resulted in an increased (8-15%) beta-A-dependent cleavage of C4. Thus our results indicate that the C1q-independent activation of C1 and C4 can be partially mediated by the activation products of contact system. Since the activation of contact system and of C4 leads to generation of several humoral inflammatory peptides, non-fibrillar beta-A might play a role in initiating the early inflammatory reactions leading to a multistep cascade contributing to neuronal and clinical dysfunction of AD brain.

  4. Alzheimer's β-amyloid peptides can activate the early components of complement classical pathway in a C1q-independent manner

    Science.gov (United States)

    Bergamaschini, L; Canziani, S; Bottasso, B; Cugno, M; Braidotti, P; Agostoni, A

    1999-01-01

    β-Amyloid (β-A) accumulates in the brain of patients with Alzheimer's disease (AD) and is presumably involved in the pathogenesis of this disease, on account of its neurotoxicity and complement-activating ability. Although assembly of β-A in particular aggregates seems to be crucial, soluble non-fibrillar β-A may also be involved. Non-fibrillar β-A does not bind C1q, so we investigated alternative mechanisms of β-A-dependent complement activation in vitro. On incubation with normal human plasma, non-fibrillar β-A 1-42, and truncated peptide 1–28, induced dose-dependent activation of C1s and C4, sparing C3, as assessed by densitometric analysis of immunostained membrane after SDS–PAGE and Western blotting. The mechanism of C4 activation was not dependent on C1q, because non-fibrillar β-A can still activate C1s and C4 in plasma genetically deficient in C1q (C1qd). In Factor XII-deficient plasma (F.XIId) the amount of cleaved C4 was about 5–10% less that in C1qd and in normal EDTA plasma; the reconstitution of F.XIId plasma with physiologic concentrations of F.XII resulted in an increased (8–15%) β-A-dependent cleavage of C4. Thus our results indicate that the C1q-independent activation of C1 and C4 can be partially mediated by the activation products of contact system. Since the activation of contact system and of C4 leads to generation of several humoral inflammatory peptides, non-fibrillar β-A might play a role in initiating the early inflammatory reactions leading to a multistep cascade contributing to neuronal and clinical dysfunction of AD brain. PMID:10193429

  5. Complement defects in patients with chronic rhinosinusitis

    DEFF Research Database (Denmark)

    Gaunsbaek, Maria Quisgaard; Lange, Bibi; Kjeldsen, Anette D;

    2012-01-01

    The complement system is an important part of our immune system, and complement defects lead generally to increased susceptibility to infections and autoimmune diseases. We have studied the role of complement activity in relation with chronic rhinosinusitis (CRS), and more specifically studied...... whether complement defects collectively predispose individuals for CRS or affect CRS severity. The participants comprised 87 CRS patients randomly selected from the general population, and a control group of 150 healthy blood donors. The CRS patients were diagnosed according to the European Position Paper...... on Rhinosinusitis and nasal Polyps criteria, and severity was evaluated by the Sino-nasal Outcome Test-22. Serum samples were analysed by ELISA for activity of the respective pathways of complement, and subsequently for serum levels of relevant components. We found that the frequency of complement defects...

  6. Humoral pattern recognition and the complement system.

    Science.gov (United States)

    Degn, S E; Thiel, S

    2013-08-01

    In the context of immunity, pattern recognition is the art of discriminating friend from foe and innocuous from noxious. The basis of discrimination is the existence of evolutionarily conserved patterns on microorganisms, which are intrinsic to these microorganisms and necessary for their function and existence. Such immutable or slowly evolving patterns are ideal handles for recognition and have been targeted by early cellular immune defence mechanisms such as Toll-like receptors, NOD-like receptors, RIG-I-like receptors, C-type lectin receptors and by humoral defence mechanisms such as the complement system. Complement is a proteolytic cascade system comprising around 35 different soluble and membrane-bound proteins. It constitutes a central part of the innate immune system, mediating several major innate effector functions and modulating adaptive immune responses. The complement cascade proceeds via controlled, limited proteolysis and conformational changes of constituent proteins through three activation pathways: the classical pathway, the alternative pathway and the lectin pathway, which converge in common effector functions. Here, we review the nature of the pattern recognition molecules involved in complement activation, as well as their close relatives with no or unknown capacity for activating complement. We proceed to examine the composition of the pattern recognition complexes involved in complement activation, focusing on those of the lectin pathway, and arrive at a new model for their mechanism of operation, supported by recently emerging evidence.

  7. On Stabilizing or Deregulating Food Prices

    OpenAIRE

    Flåm, Sjur Didrik; Gaasland, Ivar; Vårdal, Erling

    2006-01-01

    This paper studies measurement of welfare e¤ects, transient and permanent, of stabilizing or deregulating prices in Cobweb-like settings. As in Cobweb-models, producers must commit inputs in face of uncertainty. Here, however, we consider producers who are concerned with adaptations of inputs rather than price predictions. This shift of emphasis reflects two things. First, since persistent randomness causes on-going price fluctuations, point predictions are of modest concern. Second, producer...

  8. An integer linear programming approach for finding deregulated subgraphs in regulatory networks.

    Science.gov (United States)

    Backes, Christina; Rurainski, Alexander; Klau, Gunnar W; Müller, Oliver; Stöckel, Daniel; Gerasch, Andreas; Küntzer, Jan; Maisel, Daniela; Ludwig, Nicole; Hein, Matthias; Keller, Andreas; Burtscher, Helmut; Kaufmann, Michael; Meese, Eckart; Lenhof, Hans-Peter

    2012-03-01

    Deregulation of cell signaling pathways plays a crucial role in the development of tumors. The identification of such pathways requires effective analysis tools that facilitate the interpretation of expression differences. Here, we present a novel and highly efficient method for identifying deregulated subnetworks in a regulatory network. Given a score for each node that measures the degree of deregulation of the corresponding gene or protein, the algorithm computes the heaviest connected subnetwork of a specified size reachable from a designated root node. This root node can be interpreted as a molecular key player responsible for the observed deregulation. To demonstrate the potential of our approach, we analyzed three gene expression data sets. In one scenario, we compared expression profiles of non-malignant primary mammary epithelial cells derived from BRCA1 mutation carriers and of epithelial cells without BRCA1 mutation. Our results suggest that oxidative stress plays an important role in epithelial cells of BRCA1 mutation carriers and that the activation of stress proteins may result in avoidance of apoptosis leading to an increased overall survival of cells with genetic alterations. In summary, our approach opens new avenues for the elucidation of pathogenic mechanisms and for the detection of molecular key players.

  9. Complement and autoimmunity.

    Science.gov (United States)

    Ballanti, Eleonora; Perricone, Carlo; Greco, Elisabetta; Ballanti, Marta; Di Muzio, Gioia; Chimenti, Maria Sole; Perricone, Roberto

    2013-07-01

    The complement system is a component of the innate immune system. Its main function was initially believed to be limited to the recognition and elimination of pathogens through direct killing or stimulation of phagocytosis. However, in recent years, the immunoregulatory functions of the complement system were demonstrated and it was determined that the complement proteins play an important role in modulating adaptive immunity and in bridging innate and adaptive responses. When the delicate mechanisms that regulate this sophisticated enzymatic system are unbalanced, the complement system may cause damage, mediating tissue inflammation. Dysregulation of the complement system has been involved in the pathogenesis and clinical manifestations of several autoimmune diseases, such as systemic lupus erythematosus, vasculitides, Sjögren's syndrome, antiphospholipid syndrome, systemic sclerosis, dermatomyositis, and rheumatoid arthritis. Complement deficiencies have been associated with an increased risk to develop autoimmune disorders. Because of its functions, the complement system is an attractive therapeutic target for a wide range of diseases. Up to date, several compounds interfering with the complement cascade have been studied in experimental models for autoimmune diseases. The main therapeutic strategies are inhibition of complement activation components, inhibition of complement receptors, and inhibition of membrane attack complex. At present, none of the available agents was proven to be both safe and effective for treatment of autoimmune diseases in humans. Nonetheless, data from preclinical studies and initial clinical trials suggest that the modulation of the complement system could constitute a viable strategy for the treatment of autoimmune conditions in the decades to come.

  10. AglH, a thermophilic UDP-N-acetylglucosamine-1-phosphate:dolichyl phosphate GlcNAc-1-phosphotransferase initiating protein N-glycosylation pathway in Sulfolobus acidocaldarius, is capable of complementing the eukaryal Alg7.

    Science.gov (United States)

    Meyer, Benjamin H; Shams-Eldin, Hosam; Albers, Sonja-Verena

    2017-01-01

    AglH, a predicted UDP-GlcNAc-1-phosphate:dolichyl phosphate GlcNAc-1-phosphotransferase, is initiating the protein N-glycosylation pathway in the thermoacidophilic crenarchaeon Sulfolobus acidocaldarius. AglH successfully replaced the endogenous GlcNAc-1-phosphotransferase activity of Alg7 in a conditional lethal Saccharomyces cerevisiae strain, in which the first step of the eukaryal protein N-glycosylation process was repressed. This study is one of the few examples of cross-domain complementation demonstrating a conserved polyprenyl phosphate transferase reaction within the eukaryal and archaeal domain like it was demonstrated for Methanococcus voltae (Shams-Eldin et al. 2008). The topology prediction and the alignment of the AglH membrane protein with GlcNAc-1-phosphotransferases from the three domains of life show significant conservation of amino acids within the different proposed cytoplasmic loops. Alanine mutations of selected conserved amino acids in the putative cytoplasmic loops II (D100), IV (F220) and V (F264) demonstrated the importance of these amino acids for cross-domain AlgH activity in in vitro complementation assays in S. cerevisiae. Furthermore, antibiotic treatment interfering directly with the activity of dolichyl phosphate GlcNAc-1-phosphotransferases confirmed the essentiality of N-glycosylation for cell survival.

  11. Complement associated pathogenic mechanisms in myasthenia gravis.

    Science.gov (United States)

    Tüzün, Erdem; Christadoss, Premkumar

    2013-07-01

    The complement system is profoundly involved in the pathogenesis of acetylcholine receptor (AChR) antibody (Ab) related myasthenia gravis (MG) and its animal model experimental autoimmune myasthenia gravis (EAMG). The most characteristic finding of muscle pathology in both MG and EAMG is the abundance of IgG and complement deposits at the nerve-muscle junction (NMJ), suggesting that AChR-Ab induces muscle weakness by complement pathway activation and consequent membrane attack complex (MAC) formation. This assumption has been supported with EAMG resistance of complement factor C3 knockout (KO), C4 KO and C5 deficient mice and amelioration of EAMG symptoms following treatment with complement inhibitors such as cobra venom factor, soluble complement receptor 1, anti-C1q, anti-C5 and anti-C6 Abs. Moreover, the complement inhibitor decay accelerating factor (DAF) KO mice exhibit increased susceptibility to EAMG. These findings have brought forward improvisation of novel therapy methods based on inhibition of classical and common complement pathways in MG treatment.

  12. The role of complement in AMD.

    Science.gov (United States)

    Zipfel, Peter F; Lauer, Nadine; Skerka, Christine

    2010-01-01

    Age related macular degeneration (AMD) is a common form of blindness in the western world and genetic variations of several complement genes, including the complement regulator Factor H, the central complement component C3, Factor B, C2, and also Factor I confer a risk for the disease. However deletion of a chromosomal segment in the Factor H gene cluster on human chromosome 1, which results in the deficiency of the terminal pathway regulator CFHR1, and of the putative complement regulator CFHR3 has a protective effect for development of AMD. The Factor H gene encodes two proteins Factor H and FHL1 which are derived from alternatively processed transcripts. In particular a sequence variation at position 402 of both Factor H and FHL1 is associated with a risk for AMD. A tyrosine residue at position 402 represents the protective and a histidine residue the risk variant. AMD is considered a chronic inflammatory disease, which can be caused by defective and inappropriate regulation of the continuously activated alternative complement pathway. This activation generates complement effector products and inflammatory mediators that stimulate further inflammatory reactions. Defective regulation can lead to formation of immune deposits, drusen and ultimately translate into damage of retinal pigment epithelial cells, rupture of the interface between these epithelial cells and the Bruch's membrane and vision loss. Here we describe the role of complement in the retina and summarize the current concept how defective or inappropriate local complement control contributes to inflammation and the pathophysiology of AMD.

  13. Molecules Great and Small: The Complement System.

    Science.gov (United States)

    Mathern, Douglas R; Heeger, Peter S

    2015-09-04

    The complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection and autoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement membrane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, which requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced by endothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressive kidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and antigen-presenting cells, produce alternative pathway complement components during cognate interactions. The subsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to their respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell-derived complement enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the pathogenesis of other T cell-mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionally been shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New translational immunology efforts along with the development of pharmacologic agents that block human complement components and receptors now permit

  14. Neuronal microRNA deregulation in response to Alzheimer's disease amyloid-beta.

    Directory of Open Access Journals (Sweden)

    Nicole Schonrock

    Full Text Available Normal brain development and function depends on microRNA (miRNA networks to fine tune the balance between the transcriptome and proteome of the cell. These small non-coding RNA regulators are highly enriched in brain where they play key roles in neuronal development, plasticity and disease. In neurodegenerative disorders such as Alzheimer's disease (AD, brain miRNA profiles are altered; thus miRNA dysfunction could be both a cause and a consequence of disease. Our study dissects the complexity of human AD pathology, and addresses the hypothesis that amyloid-beta (Abeta itself, a known causative factor of AD, causes neuronal miRNA deregulation, which could contribute to the pathomechanisms of AD. We used sensitive TaqMan low density miRNA arrays (TLDA on murine primary hippocampal cultures to show that about half of all miRNAs tested were down-regulated in response to Abeta peptides. Time-course assays of neuronal Abeta treatments show that Abeta is in fact a powerful regulator of miRNA levels as the response of certain mature miRNAs is extremely rapid. Bioinformatic analysis predicts that the deregulated miRNAs are likely to affect target genes present in prominent neuronal pathways known to be disrupted in AD. Remarkably, we also found that the miRNA deregulation in hippocampal cultures was paralleled in vivo by a deregulation in the hippocampus of Abeta42-depositing APP23 mice, at the onset of Abeta plaque formation. In addition, the miRNA deregulation in hippocampal cultures and APP23 hippocampus overlaps with those obtained in human AD studies. Taken together, our findings suggest that neuronal miRNA deregulation in response to an insult by Abeta may be an important factor contributing to the cascade of events leading to AD.

  15. Activation of the alternative complement pathway in canine normal serum by Paracoccidioides brasiliensis Ativação da via alternativa do complemento em soro de cão normal por Paracoccidioides brasiliensis

    Directory of Open Access Journals (Sweden)

    A.A.C. Bianchini

    2009-06-01

    Full Text Available The dimorphic fungus Paracoccidioides brasiliensis is the etiological agent of paracoccidioidomycosis, a human granulomatous disease. Recently the first case of natural disease in dogs was reported. The complement system is an important effector component of humoral immunity against infectious agents. Therefore, the aim of this study was to evaluate the activation of the dog alternative complement pathway by P. brasiliensis. Initially, the ability of erythrocytes of guinea pig, rabbit, sheep, chicken and swine to activate the dog alternative pathway was evaluated. The guinea pig erythrocytes showed the greatest capacity to activate dog alternative pathway. The alternative (AH50 hemolytic activity was evaluated in 27 serum samples from healthy dogs and the mean values were 87.2 AH50/ml. No significant differences were observed in relation to sex and age. The alternative pathway activation by P. brasiliensis was higher in serum samples from adult dogs when compared to puppies and aged dogs (p O fungo dimórfico Paracoccidioides brasiliensis é o agente etiológico da paracoccidioidomicose, uma doença granulomatosa humana. Recentemente, foi relatado o primeiro caso da doença natural em cães. O sistema complemento é um importante componente efetor da imunidade humoral contra agentes infecciosos. Portanto, o objetivo deste trabalho foi avaliar a ativação da via alternativa do complemento canina pelo P. brasiliensis. Inicialmente, foi avaliada a capacidade de eritrócitos de cobaia, coelho, carneiro, galinha e suíno ativarem a via alternativa do complemento canino. Os eritrócitos de cobaia apresentaram maior capacidade de ativar a via alternative do complemento canino. A atividade hemolítica da via alternativa (AH50 foi avaliada em 27 amostras de soro de cães saldáveis e os valores médios observados foram de 87,2 AH50/ml. Não foi observada diferença significativa ao sexo e idade. A ativação da via alternativa pelo P. brasiliensis foi

  16. Complement defects in patients with chronic rhinosinusitis.

    Directory of Open Access Journals (Sweden)

    Maria Q Gaunsbaek

    Full Text Available The complement system is an important part of our immune system, and complement defects lead generally to increased susceptibility to infections and autoimmune diseases. We have studied the role of complement activity in relation with chronic rhinosinusitis (CRS, and more specifically studied whether complement defects collectively predispose individuals for CRS or affect CRS severity. The participants comprised 87 CRS patients randomly selected from the general population, and a control group of 150 healthy blood donors. The CRS patients were diagnosed according to the European Position Paper on Rhinosinusitis and nasal Polyps criteria, and severity was evaluated by the Sino-nasal Outcome Test-22. Serum samples were analysed by ELISA for activity of the respective pathways of complement, and subsequently for serum levels of relevant components. We found that the frequency of complement defects was significantly higher among CRS patients than among healthy control subjects. A majority of Mannan-binding lectin deficient CRS patients was observed. The presence of complement defects had no influence on the severity of subjective symptoms. Our studies show that defects in the complement system collectively may play an immunological role related to the development of CRS. However, an association between severity of symptoms and presence of complement defects could not be demonstrated.

  17. Complement-mediated solubilization of immune complexes and their interaction with complement C3 receptors

    DEFF Research Database (Denmark)

    Petersen, Ivan; Baatrup, Gunnar; Jepsen, H H;

    1985-01-01

    Some of the molecular events in the complement (C)-mediated solubilization of immune complexes (IC) have been clarified in recent years. The solubilization is primarily mediated by alternative C pathway proteins whereas factors in the classical pathway accelerate the process. Components of the me......Some of the molecular events in the complement (C)-mediated solubilization of immune complexes (IC) have been clarified in recent years. The solubilization is primarily mediated by alternative C pathway proteins whereas factors in the classical pathway accelerate the process. Components...

  18. National policy in a deregulated marketplace

    Energy Technology Data Exchange (ETDEWEB)

    Jensen, V. [Dept. of Energy, Washington, DC (United States)

    1996-12-31

    This paper is one of three keynote presentations given at the conference. It briefly discusses government policy issues regarding electric utility deregulation. Three major questions are examined: (1) policies and institutions required to ensure a free market, (2) allocation of stranded assets and ensuring that consumers benefit from restructuring, and (3) continuation of collateral utility activities such as low income program investments, energy efficiency, and renewable energy use. Types of policy options under consideration are reviewed, and potential state and federal roles are described.

  19. Properdin in complement activation and tissue injury.

    Science.gov (United States)

    Lesher, Allison M; Nilsson, Bo; Song, Wen-Chao

    2013-12-15

    The plasma protein properdin is the only known positive regulator of complement activation. Although regarded as an initiator of the alternative pathway of complement activation at the time of its discovery more than a half century ago, the role and mechanism of action of properdin in the complement cascade has undergone significant conceptual evolution since then. Despite the long history of research on properdin, however, new insight and unexpected findings on the role of properdin in complement activation, pathogen infection and host tissue injury are still being revealed by ongoing investigations. In this article, we provide a brief review on recent studies that shed new light on properdin biology, focusing on the following three topics: (1) its role as a pattern recognition molecule to direct and trigger complement activation, (2) its context-dependent requirement in complement activation on foreign and host cell surfaces, and (3) its involvement in alternative pathway complement-mediated immune disorders and considerations of properdin as a potential therapeutic target in human diseases.

  20. Lymphocytes as liver damage mirror of HCV related adipogenesis deregulation.

    Directory of Open Access Journals (Sweden)

    Antonella Minutolo

    Full Text Available Hepatitis C virus infection leads to a wide spectrum of liver diseases ranging from mild chronic hepatitis to end-stage cirrhosis and hepatocellular carcinoma. An intriguing aspect of the HCV infection is its close connection with lipid metabolism playing an important role in the HCV life cycle and in its pathogenesis. HCV is known to be a hepatotropic virus; however, it can also infect peripheral blood mononuclear cells (PBMCs. The goal of the current investigation is to compare the adipogenesis profile of liver tissues to lymphocytes of HCV infected patients, in order to understand if PBMCs may reflect the alterations of intracellular pathways occurring during HCV-related liver steatosis. Using the Human Adipogenesis PCR Array, gene expression was analyzed in liver samples and PBMCs of chronic HCV+, HBV+ and Healthy Donors (HDs patients. We observed a similar modulation of lipid metabolism in HCV+ and HBV+liver tissues and lymphoid, cells suggesting that PBMCs reflect the liver adipogenesis deregulation related to infection, even if the two viruses have a different impact in the regulation of the adipogenesis mechanisms. In particular, some genes involved in lipid metabolism and inflammation, as well as in cell transformation, were up-regulated, in a similar way, in both HCV models analyzed. Interestingly, these genes were positively correlated to virological and hepatic functional parameters of HCV+ patients. On the contrary, HBV+ patients displayed a completely different profile. PBMCs of HCV+ patients seem to be useful model to study how HCV-related lipid metabolism deregulation occurs in liver. The obtained data suggest some molecules as new possible biomarkers of HCV-related liver damage progression.

  1. Surviving mousepox infection requires the complement system.

    Directory of Open Access Journals (Sweden)

    Elizabeth A Moulton

    2008-12-01

    Full Text Available Poxviruses subvert the host immune response by producing immunomodulatory proteins, including a complement regulatory protein. Ectromelia virus provides a mouse model for smallpox where the virus and the host's immune response have co-evolved. Using this model, our study investigated the role of the complement system during a poxvirus infection. By multiple inoculation routes, ectromelia virus caused increased mortality by 7 to 10 days post-infection in C57BL/6 mice that lack C3, the central component of the complement cascade. In C3(-/- mice, ectromelia virus disseminated earlier to target organs and generated higher peak titers compared to the congenic controls. Also, increased hepatic inflammation and necrosis correlated with these higher tissue titers and likely contributed to the morbidity in the C3(-/- mice. In vitro, the complement system in naïve C57BL/6 mouse sera neutralized ectromelia virus, primarily through the recognition of the virion by natural antibody and activation of the classical and alternative pathways. Sera deficient in classical or alternative pathway components or antibody had reduced ability to neutralize viral particles, which likely contributed to increased viral dissemination and disease severity in vivo. The increased mortality of C4(-/- or Factor B(-/- mice also indicates that these two pathways of complement activation are required for survival. In summary, the complement system acts in the first few minutes, hours, and days to control this poxviral infection until the adaptive immune response can react, and loss of this system results in lethal infection.

  2. Electricity deregulation may leave poor in dark

    Energy Technology Data Exchange (ETDEWEB)

    Brockway, N. [National Consumer Law Center, Boston, MA (United States)

    1997-12-31

    The biggest customers will wield the most power in a deregulated electricity environment. How will the low-income consumer fare? {open_quotes}Policymakers will have to provide mechanisms to prevent competing retail electrical providers from unfairly discriminating against rate payers that utilities regard as high risks,{close_quotes} says Nancy Brockway, a utility analyst and staff attorney for the National Consumer Law Center in Boston, Massachusetts. Fortunately, most electric utilities already recognize that low-income customers usually pay their bills on time and represent a lucrative market. But there will be a need for safeguards. One possible approach is to provide a safety-net fund. {open_quotes}In its most flexible form, the safety net could reflect a `pay-or-play` system, in which suppliers would have the choice of contributing to the fund or serving safety-net customers,{close_quotes} Brockway says. {open_quotes}In their push for deregulation, policymakers have acknowledged the importance of energy-management programs for low-income customers, regardless of how the future electric industry is configured.{close_quotes}

  3. Deregulated lncRNAs in B Cells from Patients with Active Tuberculosis

    Science.gov (United States)

    Fu, Yurong; Xu, Xianqin; Xue, Junfang; Duan, Wenping; Yi, Zhengjun

    2017-01-01

    Role of lncRNAs in human adaptive immune response to TB infection is largely unexplored. To address this issue, here we characterized lncRNA expression profile in primary human B cell response to TB infection using microarray assay. Several lncRNAs and mRNAs were chosen for RT-qPCR validation. Bioinformatics prediction was applied to delineate function of the deregulated mRNAs. We found that 844 lncRNAs and 597 mRNAs were differentially expressed between B cell samples from individuals with or without TB. KEGG pathway analysis for the deregulated mRNAs indicated a number of pathways, such as TB, TLR signaling pathway and antigen processing and presentation. Moreover, corresponding to the dysregulation of many lncRNAs, we also found that their adjacent protein-coding genes were also deregulated. Functional annotation for the corresponding mRNAs showed that these lncRNAs were mainly associated with TLR signaling, TGF-β signaling. Interestingly, SOCS3, which is a critical negative regulator of cytokine response to TB infection and its nearby lncRNA XLOC_012582, were highly expressed in active TB B cells. Subsequent RT-qPCR results confirmed the changes. Whether upregulated XLOC_012582 causes SOCS3 overexpression and is eventually involved in the context of exacerbations of active TB represents an interesting issue that deserves to be further explored. Taken together, for the first time, we identified a set of deregulated lncRNAs in active TB B cells and their functions were predicted. Such findings provided novel insight into the pathogenesis of TB and further studies should focus on the function and pathogenic mechanisms of the lncRNAs involved in active TB. PMID:28125665

  4. The role of complement in experimental autoimmune myasthenia gravis

    Science.gov (United States)

    Kusner, Linda L.; Kaminski, Henry J.

    2012-01-01

    Complement plays an important role in the pathophysiology of experimental autoimmune myasthenia gravis (EAMG). The deposition of IgG at the neuromuscular junction, followed by the activation and observance of C3 at the site, and finally the insertion of the membrane attack complex, which results in the destruction of the plasma membrane at the neuromuscular junction. Animal models’ of complement-deficient components show the importance of the mediated lysisin EAMG. These events have regulators that allow for the limitation in the cascade and the ability of the cell to inhibit complement at many places along the pathway. The complement regulatory proteins have many roles in reducing the activation of the complement cascade and the inflammatory pathways. Mice deficient in complement regulatory proteins, decay accelerating factor and CD59, demonstrate a significant increase in the destruction at the neuromuscular junction. Inhibition of complement-mediated lysis is an attractive therapeutic in MG. PMID:23252907

  5. Role of complement and complement regulatory proteins in the complications of diabetes.

    Science.gov (United States)

    Ghosh, Pamela; Sahoo, Rupam; Vaidya, Anand; Chorev, Michael; Halperin, Jose A

    2015-06-01

    It is well established that the organ damage that complicates human diabetes is caused by prolonged hyperglycemia, but the cellular and molecular mechanisms by which high levels of glucose cause tissue damage in humans are still not fully understood. The prevalent hypothesis explaining the mechanisms that may underlie the pathogenesis of diabetes complications includes overproduction of reactive oxygen species, increased flux through the polyol pathway, overactivity of the hexosamine pathway causing intracellular formation of advanced glycation end products, and activation of protein kinase C isoforms. In addition, experimental and clinical evidence reported in past decades supports a strong link between the complement system, complement regulatory proteins, and the pathogenesis of diabetes complications. In this article, we summarize the body of evidence that supports a role for the complement system and complement regulatory proteins in the pathogenesis of diabetic vascular complications, with specific emphasis on the role of the membrane attack complex (MAC) and of CD59, an extracellular cell membrane-anchored inhibitor of MAC formation that is inactivated by nonenzymatic glycation. We discuss a pathogenic model of human diabetic complications in which a combination of CD59 inactivation by glycation and hyperglycemia-induced complement activation increases MAC deposition, activates pathways of intracellular signaling, and induces the release of proinflammatory, prothrombotic cytokines and growth factors. Combined, complement-dependent and complement-independent mechanisms induced by high glucose promote inflammation, proliferation, and thrombosis as characteristically seen in the target organs of diabetes complications.

  6. Therapeutic complement inhibition in complement-mediated hemolytic anemias: Past, present and future.

    Science.gov (United States)

    Risitano, Antonio M; Marotta, Serena

    2016-06-01

    The introduction in the clinic of anti-complement agents represented a major achievement which gave to physicians a novel etiologic treatment for different human diseases. Indeed, the first anti-complement agent eculizumab has changed the treatment paradigm of paroxysmal nocturnal hemoglobinuria (PNH), dramatically impacting its severe clinical course. In addition, eculizumab is the first agent approved for atypical Hemolytic Uremic Syndrome (aHUS), a life-threatening inherited thrombotic microangiopathy. Nevertheless, such remarkable milestone in medicine has brought to the fore additional challenges for the scientific community. Indeed, the list of complement-mediated anemias is not limited to PNH and aHUS, and other human diseases can be considered for anti-complement treatment. They include other thrombotic microangiopathies, as well as some antibody-mediated hemolytic anemias. Furthermore, more than ten years of experience with eculizumab led to a better understanding of the individual steps of the complement cascade involved in the pathophysiology of different human diseases. Based on this, new unmet clinical needs are emerging; a number of different strategies are currently under development to improve current anti-complement treatment, trying to address these specific clinical needs. They include: (i) alternative anti-C5 agents, which may improve the heaviness of eculizumab treatment; (ii) broad-spectrum anti-C3 agents, which may improve the efficacy of anti-C5 treatment by intercepting the complement cascade upstream (i.e., preventing C3-mediated extravascular hemolysis in PNH); (iii) targeted inhibitors of selective complement activating pathways, which may prevent early pathogenic events of specific human diseases (e.g., anti-classical pathway for antibody-mediated anemias, or anti-alternative pathway for PNH and aHUS). Here we briefly summarize the status of art of current and future complement inhibition for different complement-mediated anemias

  7. TMA: beware of complements.

    Science.gov (United States)

    Ricklin, Daniel; Cines, Douglas B

    2013-09-19

    In this issue of Blood, Jodele and colleagues report that defective complement regulation contributes to the development of thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (HSCT) with important implications for diagnosis and management of this severe clinical complication.

  8. Dispatch Liquidity Theory in a Deregulated Environment

    Institute of Scientific and Technical Information of China (English)

    SHEN Yu; XIA Qing; KANG Chongqing

    2005-01-01

    Power system security and reliability are more complex issues in a deregulated environment. Various criteria have been considered for power system reliability. In the day-ahead market, a successful trade schedule should be able to accept various disturbances with sufficient flexibility to be adjusted during the re-dispatch process. This paper describes the dispatch liquidity theory and some liquidity indices. The liquidity indices evaluate the effective operating reserves with the network constraints taken into consideration. A model is presented to calculate the liquidity index. An extended trade scheduling model with minimum liquidity index constraints is presented that considers the distribution requirements of the operating reserves. The liquidity indices could also be used to coordinate the security and reliability between multistage markets and for contingency selection. The algorithms were tested with real power system data. The results show that the dispatch liquidity theory is reasonable and the algorithms are effective.

  9. Factor H-related proteins determine complement-activating surfaces.

    Science.gov (United States)

    Józsi, Mihály; Tortajada, Agustin; Uzonyi, Barbara; Goicoechea de Jorge, Elena; Rodríguez de Córdoba, Santiago

    2015-06-01

    Complement factor H-related proteins (FHRs) are strongly associated with different diseases involving complement dysregulation, which suggests a major role for these proteins regulating complement activation. Because FHRs are evolutionarily and structurally related to complement inhibitor factor H (FH), the initial assumption was that the FHRs are also negative complement regulators. Whereas weak complement inhibiting activities were originally reported for these molecules, recent developments indicate that FHRs may enhance complement activation, with important implications for the role of these proteins in health and disease. We review these findings here, and propose that FHRs represent a complex set of surface recognition molecules that, by competing with FH, provide improved discrimination of self and non-self surfaces and play a central role in determining appropriate activation of the complement pathway.

  10. p27: a barometer of signaling deregulation and potential predictor of response to targeted therapies.

    Science.gov (United States)

    Wander, Seth A; Zhao, Dekuang; Slingerland, Joyce M

    2011-01-01

    Phosphorylation of the cyclin-dependent kinase inhibitor p27 by upstream mitogenic signaling pathways regulates its stability, localization, and biological function. In human cancers, loss of the antiproliferative action of p27 can arise through reduced protein levels and/or cytoplasmic mislocalization, leading to increased cell proliferation and/or cell migration, respectively. Reduced p27 expression levels and p27 mislocalization have potential prognostic and therapeutic implications in various types of human cancers. This review highlights mechanisms of functional deregulation of p27 by oncogenic signaling that provide an important molecular rationale for pathway targeting in cancer treatment.

  11. Autocrine Effects of Tumor-Derived Complement

    Directory of Open Access Journals (Sweden)

    Min Soon Cho

    2014-03-01

    Full Text Available We describe a role for the complement system in enhancing cancer growth. Cancer cells secrete complement proteins that stimulate tumor growth upon activation. Complement promotes tumor growth via a direct autocrine effect that is partially independent of tumor-infiltrating cytotoxic T cells. Activated C5aR and C3aR signal through the PI3K/AKT pathway in cancer cells, and silencing the PI3K or AKT gene in cancer cells eliminates the progrowth effects of C5aR and C3aR stimulation. In patients with ovarian or lung cancer, higher tumoral C3 or C5aR mRNA levels were associated with decreased overall survival. These data identify a role for tumor-derived complement proteins in promoting tumor growth, and they therefore have substantial clinical and therapeutic implications.

  12. Gas and electricity 2000: energy deregulation; Gaz et electricite 2000: deregulation energie

    Energy Technology Data Exchange (ETDEWEB)

    Hulot, J.C. [Ministere de l' Industrie et de l' Amenagement du Territoire, 75 - Paris (France); Charbit, N. [Allen and Overy, 75 - Paris (France); Tuot, Th. [CRE, Commission de Regulation de l' Electricite, 75 - Paris (France)] [and others

    2000-11-01

    This document brings together 17 testimonies of experts about the deregulation of the gas and electricity markets. Content: 1 - the new rules controlling the market: schedule and regulatory evolutions, the new legal framework, the new regulation, the missions and competences of the Commission of Electricity Regulation; 2 - the new commercial practices: the question of electricity transport and of the network independence, the development of trading, the stock exchanges and the forecasting of Paris market, the correlations with the environment (eco-taxes and climate change); 3 - the proposals of new actors: the contribution of a deregulated market like Spain, the comparison with a fully open market like Germany, an internal out-sourcing example to create an energy entity as a whole, the role of a bank in the risk management and the derived markets, the contribution of new technologies from service suppliers; 4 - the consumers attitude with respect to new offers: the historical gas and electricity utilities at the service of French and European clients, the new opportunities offered by the deregulation, the contribution of an independent supplier to consumers, the expectations of big companies and eligible consumers. (J.S.)

  13. Infections Revealing Complement Deficiency in Adults

    Science.gov (United States)

    Audemard-Verger, A.; Descloux, E.; Ponard, D.; Deroux, A.; Fantin, B.; Fieschi, C.; John, M.; Bouldouyre, A.; Karkowsi, L.; Moulis, G.; Auvinet, H.; Valla, F.; Lechiche, C.; Davido, B.; Martinot, M.; Biron, C.; Lucht, F.; Asseray, N.; Froissart, A.; Buzelé, R.; Perlat, A.; Boutboul, D.; Fremeaux-Bacchi, V.; Isnard, S.; Bienvenu, B.

    2016-01-01

    Abstract Complement system is a part of innate immunity, its main function is to protect human from bacterial infection. As genetic disorders, complement deficiencies are often diagnosed in pediatric population. However, complement deficiencies can also be revealed in adults but have been poorly investigated. Herein, we describe a case series of infections revealing complement deficiency in adults to study clinical spectrum and management of complement deficiencies. A nationwide retrospective study was conducted in French university and general hospitals in departments of internal medicine, infectious diseases enrolling patients older than 15 years old who had presented at least one infection leading to a complement deficiency diagnosis. Forty-one patients included between 2002 and 2015 in 19 different departments were enrolled in this study. The male-to-female ratio was 1.3 and the mean age at diagnosis was 28 ± 14 (15–67) years. The main clinical feature was Neisseria meningitidis meningitis 75% (n = 31/41) often involving rare serotype: Y (n = 9) and W 135 (n = 7). The main complement deficiency observed was the common final pathway deficiency 83% (n = 34/41). Half of the cohort displayed severe sepsis or septic shock at diagnosis (n = 22/41) but no patient died. No patient had family history of complement deficiency. The mean follow-up was 1.15 ± 1.95 (0.1–10) years. Half of the patients had already suffered from at least one infection before diagnosis of complement deficiency: meningitis (n = 13), pneumonia (n = 4), fulminans purpura (n = 1), or recurrent otitis (n = 1). Near one-third (n = 10/39) had received prophylactic antibiotics (cotrimoxazole or penicillin) after diagnosis of complement deficiency. The vaccination coverage rate, at the end of the follow-up, for N meningitidis, Streptococcus pneumonia, and Haemophilius influenzae were, respectively, 90% (n = 33/37), 47% (n = 17/36), and 35

  14. Complement genetics, deficiencies, and disease associations.

    Science.gov (United States)

    Mayilyan, Karine R

    2012-07-01

    The complement system is a key component of innate immunity. More than 45 genes encoding the proteins of complement components or their isotypes and subunits, receptors, and regulators have been discovered. These genes are distributed throughout different chromosomes, with 19 genes comprising three significant complement gene clusters in the human genome. Genetic deficiency of any early component of the classical pathway (C1q, C1r/s, C2, C4, and C3) is associated with autoimmune diseases due to the failure of clearance of immune complexes (IC) and apoptotic materials, and the impairment of normal humoral response. Deficiencies of mannan-binding lectin (MBL) and the early components of the alternative (factor D, properdin) and terminal pathways (from C3 onward components: C5, C6, C7, C8, C9) increase susceptibility to infections and their recurrence. While the association of MBL deficiency with a number of autoimmune and infectious disorders has been well established, the effects of the deficiency of other lectin pathway components (ficolins, MASPs) have been less extensively investigated due to our incomplete knowledge of the genetic background of such deficiencies and the functional activity of those components. For complement regulators and receptors, the consequences of their genetic deficiency vary depending on their specific involvement in the regulatory or signalling steps within the complement cascade and beyond. This article reviews current knowledge and concepts about the genetic load of complement component deficiencies and their association with diseases. An integrative presentation of genetic data with the latest updates provides a background to further investigations of the disease association investigations of the complement system from the perspective of systems biology and systems genetics.

  15. Finite Complements in English

    Institute of Scientific and Technical Information of China (English)

    Ronald W. Langacker

    2008-01-01

    This paper explores the conceptual basis of finite complimentation in English.It first considem the distinguishing property of a finite clause,namely grounding,effeeted by tense and the modals.Notions crucial for clausal grounding--including a reality conception and the striving for control at the effective and epistemic levelsalso figure in the semantic import of eomplementation.An essential feature of complement constructions is the involvement of multiple conceptualizers,each with their own conception of reality.The different types of complement and their grammatical markings can be characterized on this basis.Finite complements differ from other types by virtue of expressing an autonomous proposition capable of being apprehended by multiple conceptualizers,each from their own vantage point.Acognitive model representing phases in the striving for epistemic control provides a partial basis for the semantic description of predicates taking finite complements.The same model supports the description of both personal and impersonal complement constructions.

  16. Internet-based Wide Area Measurement Applications in Deregulated Power Systems

    OpenAIRE

    Khatib, Abdel Rahman Amin

    2002-01-01

    Internet-Based Wide Area Measurement Applications in Deregulated Power Systems Abdel-Rahman Amin Khatib Abstract Since the deregulation of power systems was started in 1989 in the UK, many countries have been motivated to undergo deregulation. The United State started deregulation in the energy sector in California back in 1996. Since that time many other states have also started the deregulation procedures in different utilities. Most of the deregulation market in the United St...

  17. MicroRNAs and deregulated gene expression networks in neurodegeneration.

    Science.gov (United States)

    Sonntag, Kai-Christian

    2010-06-18

    Neurodegeneration is characterized by the progressive loss of neuronal cell types in the nervous system. Although the main cause of cell dysfunction and death in many neurodegenerative diseases is not known, there is increasing evidence that their demise is a result of a combination of genetic and environmental factors which affect key signaling pathways in cell function. This view is supported by recent observations that disease-compromised cells in late-stage neurodegeneration exhibit profound dysregulation of gene expression. MicroRNAs (miRNAs) introduce a novel concept of regulatory control over gene expression and there is increasing evidence that they play a profound role in neuronal cell identity as well as multiple aspects of disease pathogenesis. Here, we review the molecular properties of brain cells derived from patients with neurodegenerative diseases, and discuss how deregulated miRNA/mRNA expression networks could be a mechanism in neurodegeneration. In addition, we emphasize that the dysfunction of these regulatory networks might overlap between different cell systems and suggest that miRNA functions might be common between neurodegeneration and other disease entities.

  18. The role of activation of the lectin pathway of complement in pathogenesy of IgA nephropathy%补体活化的凝集素途径在IgA肾病发病中的作用

    Institute of Scientific and Technical Information of China (English)

    张伟; 王墨; 李秋

    2011-01-01

    To investigate the mechanism of activation the lectin pathway of complement in IgA nephropathy,enzyme-linked immunosorbent assay was performed to detect mining level of serumal mannose-binding lectin (MBL); immunohistochemical method was performed to detect expression of MBL、MASP-1、C3、Clq、IgA and C5b-9 on renal specimens. Patients of IgAN were characterized into MBL-positive cases and MBL-negative cases by glomerular co-deposition of MBL and MASP, and were analyzed distinction of couch expressionition retrospectively. Glomerular deposition of MBL was observed in 22 of 53 cases (41.5%) with IgAN and showed a mesangial pattern. All MBL-positive cases, but none of the MBL-negative cases showed glomerular co-deposition of MBLassociated serine proteases, C3 and C5b-9. Among patients of IgAN, serum level of MBL did not show significant difference than unimpaired patients. Patients of IgAN with glomerular MBL deposition, pathology classification was not correlation with intension of MBL deposition. Intension of MBL deposition was positive correlation with IgA in patients of IgAN. MBL-positive cases have significantly more proteinuria and more attacking macroscopic hematuria as MBL-negative cases, which shows activation of the mero-lectin pathway of complement is significant in IgA nephropathy.%目的 探讨补体活化的凝集素途径在IgA1肾病发病中的作用.方法 用ELISA方法 检测20例IgAN患儿和正常儿童血清的MBL水平,免疫组化检测53例IgA肾病、23例非IgA沉积肾小球疾病患儿1肾组织甘露聚糖结合凝集素(MBL)、MBL相关的丝氨酸蛋白酶(MASP-1)、C3、C1q、IgA和C5b-9的表达,了解有无MBL-MASP-1途径补体活化参与IgAN发病;回顾性分析MBL-MASP-1沉积阳性组和MBL-MASP-1沉积阴性组患儿不同临床表现的差异;分析IgAN的MBL沉积强度与病理分级的相关性,了解不同程度补体活化与IgAN病理损害的关系.结果 22例IgAN患儿肾小球有MBL、MASP-1、C3和C5b-9

  19. Bidding Strategy for Deregulated Power Markets

    Directory of Open Access Journals (Sweden)

    Preeti

    2016-07-01

    Full Text Available Load and Price forecasting play a vital role in enhancing the energy-efficient and reliable operation of electricity companies. This paper proposes a bidding strategy based on Short-Term Load Forecasting and Short-Term Price Forecasting technique used in the deregulated electricity market. The main aim of the proposed approach is to forecast load and price so as to enhance the efficiency of the power system. The input variables which are taken into account include the past load, weather and calendar data and price bidding on an hourly basis. A comparison of the accuracy of fuzzy, artificial neural network and state estimation technique is performed on the two datasets of the electricity markets of IEEE Reliability Test System and Haryana State Load Dispatch Centre. The forecasted load and price aids in increasing the profits by judiciously utilizing the generators with less cost in periods of high demand. Price forecasts are used to determine the cost of electric power and hence, plan the budget according to the consumption of power over the scheduled interval.

  20. Self-interest, deregulation and trust

    Directory of Open Access Journals (Sweden)

    Salvör Nordal

    2009-11-01

    Full Text Available In this paper I will discuss Milton Friedman’s thesis that the social responsibilityof business is to maximize the shareholders’ profit. I examine the underlyingassumption of self-interest and argue, contrary to the neoliberal thesis ofderegulation, that the profit motive must be constrained by strong state regulations.Furthermore it facilitates keeping the division between business andgovernment intact. The financial crisis shows that the emphasis on a profitmotive without the external constraints of tight regulations has serious implicationsfor the trustworthiness of business. In the latter part of the paper I willdiscuss trust in relation to self-interest. The overemphasis on self-interest isparticularly unfortunate in connection with business, and not least the financialsector, as this institution is grounded in trust, without which it cannot survive.Seen from this angle, it can be claimed that a business model, celebratingprimarily self-interest, profit-motive and deregulation, is not going to be sustainablein the long run.http://dx.doi.org/10.5324/eip.v3i2.1719

  1. Complement regulators in human disease: lessons from modern genetics.

    Science.gov (United States)

    K Liszewski, M; Atkinson, J P

    2015-03-01

    First identified in human serum in the late 19th century as a 'complement' to antibodies in mediating bacterial lysis, the complement system emerged more than a billion years ago probably as the first humoral immune system. The contemporary complement system consists of nearly 60 proteins in three activation pathways (classical, alternative and lectin) and a terminal cytolytic pathway common to all. Modern molecular biology and genetics have not only led to further elucidation of the structure of complement system components, but have also revealed function-altering rare variants and common polymorphisms, particularly in regulators of the alternative pathway, that predispose to human disease by creating 'hyperinflammatory complement phenotypes'. To treat these 'complementopathies', a monoclonal antibody against the initiator of the membrane attack complex, C5, has received approval for use. Additional therapeutic reagents are on the horizon.

  2. Industrial Deregulation, Skill Upgrading, and Wage Inequality in India

    OpenAIRE

    Rubiana Chamarbagwala; Gunjan Sharma

    2008-01-01

    We investigate the relationship between economic deregulation (delicensing), skill upgrading, and wage inequality during the 1980s and 1990s in India. We use a unique dataset on India's industrial licensing regime to test whether industrial deregulation during the 1980s and 1990s played a role in generating demand for skilled workers, as measured by the employment and wagebill shares of white-collar workers, and in raising the returns to skilled labor, as measured by the skill premium. Our an...

  3. The Role of Complement System in Septic Shock

    Directory of Open Access Journals (Sweden)

    Jean Charchaflieh

    2012-01-01

    Full Text Available Septic shock is a critical clinical condition with a high mortality rate. A better understanding of the underlying mechanisms is important to develop effective therapies. Basic and clinical studies suggest that activation of complements in the common cascade, for example, complement component 3 (C3 and C5, is involved in the development of septic shock. The involvement of three upstream complement pathways in septic shock is more complicated. Both the classical and alternative pathways appear to be activated in septic shock, but the alternative pathway may be activated earlier than the classical pathway. Activation of these two pathways is essential to clear endotoxin. Recent investigations have shed light on the role of lectin complement pathway in septic shock. Published reports suggest a protective role of mannose-binding lectin (MBL against sepsis. Our preliminary study of MBL-associated serine protease-2 (MASP-2 in septic shock patients indicated that acute decrease of MASP-2 in the early phase of septic shock might correlate with in-hospital mortality. It is unknown whether excessive activation of these three upstream complement pathways may contribute to the detrimental effects in septic shock. This paper also discusses additional complement-related pathogenic mechanisms and intervention strategies for septic shock.

  4. Complement Factor B Mutations in Atypical Hemolytic Uremic Syndrome—Disease-Relevant or Benign?

    Science.gov (United States)

    Marinozzi, Maria Chiara; Vergoz, Laura; Rybkine, Tania; Ngo, Stephanie; Bettoni, Serena; Pashov, Anastas; Cayla, Mathieu; Tabarin, Fanny; Jablonski, Mathieu; Hue, Christophe; Smith, Richard J.; Noris, Marina; Halbwachs-Mecarelli, Lise; Donadelli, Roberta; Fremeaux-Bacchi, Veronique

    2014-01-01

    Atypical hemolytic uremic syndrome (aHUS) is a genetic ultrarare renal disease associated with overactivation of the alternative pathway of complement. Four gain-of-function mutations that form a hyperactive or deregulated C3 convertase have been identified in Factor B (FB) ligand binding sites. Here, we studied the functional consequences of 10 FB genetic changes recently identified from different aHUS cohorts. Using several tests for alternative C3 and C5 convertase formation and regulation, we identified two gain-of-function and potentially disease-relevant mutations that formed either an overactive convertase (M433I) or a convertase resistant to decay by FH (K298Q). One mutation (R178Q) produced a partially cleaved protein with no ligand binding or functional activity. Seven genetic changes led to near-normal or only slightly reduced ligand binding and functional activity compared with the most common polymorphism at position 7, R7. Notably, none of the algorithms used to predict the disease relevance of FB mutations agreed completely with the experimental data, suggesting that in silico approaches should be undertaken with caution. These data, combined with previously published results, suggest that 9 of 15 FB genetic changes identified in patients with aHUS are unrelated to disease pathogenesis. This study highlights that functional assessment of identified nucleotide changes in FB is mandatory to confirm disease association. PMID:24652797

  5. Hemolytic plate assay for quantification of active human complement component C3 using methylamine-treated plasma as complement source

    DEFF Research Database (Denmark)

    Ploug, M; Jessen, T E; Welinder, K. G.

    1985-01-01

    A hemolytic plate assay specific for active human complement component C3 is described. The method is well suited for tracing active C3 during preparative purification or for screening of plasma samples. The assay is based on activation of the alternative pathway of complement by unmodified rabbi...

  6. The Complement System in Lupus Nephritis.

    Science.gov (United States)

    Birmingham, Daniel J; Hebert, Lee A

    2015-09-01

    The complement system is composed of a family of soluble and membrane-bound proteins that historically has been viewed as a key component of the innate immune system, with a primary role of providing a first-line defense against microorganisms. Although this role indeed is important, complement has many other physiological roles, including the following: (1) influencing appropriate immune responses, (2) disposing of waste in the circulation (immune complexes, cellular debris), and (3) contributing to damage of self-tissue through inflammatory pathways. These three roles are believed to be significant factors in the pathogenesis of systemic lupus erythematosus, particularly its renal manifestation (lupus nephritis), contributing both protective and damaging effects. In this review, we provide an overview of the human complement system and its functions, and discuss its intricate and seemingly contradictory roles in the pathogenesis of lupus nephritis.

  7. Characterization of the complement inhibitory function of rhesus rhadinovirus complement control protein (RCP).

    Science.gov (United States)

    Okroj, Marcin; Mark, Linda; Stokowska, Anna; Wong, Scott W; Rose, Nicola; Blackbourn, David J; Villoutreix, Bruno O; Spiller, O Brad; Blom, Anna M

    2009-01-02

    Rhesus rhadinovirus (RRV) is currently the closest known, fully sequenced homolog of human Kaposi sarcoma-associated herpesvirus. Both these viruses encode complement inhibitors as follows: Kaposi sarcoma-associated herpesvirus-complement control protein (KCP) and RRV-complement control protein (RCP). Previously we characterized in detail the functional properties of KCP as a complement inhibitor. Here, we performed comparative analyses for two variants of RCP protein, encoded by RRV strains H26-95 and 17577. Both RCP variants and KCP inhibited human and rhesus complement when tested in hemolytic assays measuring all steps of activation via the classical and the alternative pathway. RCP variants from both RRV strains supported C3b and C4b degradation by factor I and decay acceleration of the classical C3 convertase, similar to KCP. Additionally, the 17577 RCP variant accelerated decay of the alternative C3 convertase, which was not seen for KCP. In contrast to KCP, RCP showed no affinity to heparin and is the first described complement inhibitor in which the binding site for C3b/C4b does not interact with heparin. Molecular modeling shows a structural disruption in the region of RCP that corresponds to the KCP-heparin-binding site. This makes RRV a superior model for future in vivo investigations of complement evasion, as RCP does not play a supportive role in viral attachment as KCP does.

  8. Activation of Complement Following Total Hip Replacement.

    Science.gov (United States)

    Thordardottir, S; Vikingsdottir, T; Bjarnadottir, H; Jonsson, H; Gudbjornsson, B

    2016-03-01

    The aim of this study was to investigate whether complement activation, via the classical and alternative pathways, occurs following a cemented total hip replacement (THR) surgery due to osteoarthritis. Blood samples were collected systematically from 12 patients - six male and six women, with a median age of 75 (range: 59-90 years) - preoperatively, 6 h post-operatively and on the first, second and third post-operative day. Total function of classical (CH50) and alternative pathways (AH50) was evaluated, along with the determination of serum concentrations of the complement proteins C3, C4, C3d, the soluble terminal complement complex (sTCC) sC5b-9, as well as C-reactive protein (CRP) and albumin. Measurements of CRP and albumin levels elucidated a marked inflammatory response following the operation. The CH50, AH50 and C3 and C4 levels were significantly lower 6 h after the surgery compared with the preoperative levels, but elevated above the preoperative levels during the following 3 days. The complement activation product C3d levels increased continually during the whole observation period, from 13.5 AU/ml (range: 8-19 AU/ml) preoperative to 20 AU/ml (range: 12-34 AU/ml) on the third post-operative day. Furthermore, we observed an increase in the sC5b-9 levels between the preoperative and the third post-operative day. These results demonstrate a significant activation of the complement system following cemented THR. Further studies are needed to elucidate the time frame and the pathogenic role of this observed complement activation.

  9. Neuroprotection from complement-mediated inflammatory damage.

    Science.gov (United States)

    Kulkarni, Amod P; Kellaway, Laurie A; Lahiri, Debomoy K; Kotwal, Girish J

    2004-12-01

    Several neurodegenerative disorders, such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease, are associated with inflammatory damage. The complex process of neuroinflammation involves various components of the immune system and the central nervous system. Particularly, brain astrocytes and microglial cells generate several inflammatory mediators like cytokines, leukotrienes, superoxide radicals, eicasonoids, and the components of the complement cascade. Complement plays an important role in the etiology of most of the neuroinflammatory disorders. To prevent long-term dysfunction inflammation in the central nervous system must be modulated with neuroprotective agents such as nonsteroidal anti-inflammatory drugs, steroids, phenolic thiazoles, nitrones, catechins, nitric oxide synthetase inhibitors, flavonoids, and phosphodiesterase inhibitors. Few drugs are found to be effective and their therapeutic benefit is hampered by side effects. Most of the neuroprotective agents are free radical scavengers and many inhibit only one or two aspects of inflammation. The complement inhibitory activity of most of these agents is either unknown or not established. Thus, there is doubt regarding their therapeutic value in most of the inflammatory disorders in which complement plays a major role. In this context the role of a multifunctional protein, vaccinia virus complement control protein (VCP), is quite significant as it may play a pivotal role in the treatment of several neuroinflammatory disorders. VCP is known to inhibit both complement pathways involved in inflammation. It is also known to inhibit cytokines and chemokines in inflammation. Our recent studies on rats demonstrate that VCP administration inhibits macrophage infiltration, reduces spinal cord destruction, and improves motor skills associated with spinal cord injury, establishing VCP as a strong candidate for neuroprotection. Thus, complement inhibitors such as VCP can serve as neuroprotective

  10. Complement system part I - molecular mechanisms of activation and regulation

    Directory of Open Access Journals (Sweden)

    Nicolas eMerle

    2015-06-01

    Full Text Available Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals. The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage. Here we discuss the recent advances describing the molecular and structural basis of activation and regulation of the complement pathways and their implication on physiology and pathology. This article will review the mechanisms of activation of alternative, classical and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins and the membrane attack complex. We will also discuss the importance of structure-function relationships using the example of atypical hemolytic uremic syndrome. Lastly we will discuss the development and benefits of therapies using complement inhibitors.

  11. Complement analysis 2016: Clinical indications, laboratory diagnostics and quality control.

    Science.gov (United States)

    Prohászka, Zoltán; Nilsson, Bo; Frazer-Abel, Ashley; Kirschfink, Michael

    2016-11-01

    In recent years, complement analysis of body fluids and biopsies, going far beyond C3 and C4, has significantly enhanced our understanding of the disease process. Such expanded complement analysis allows for a more precise differential diagnosis and for critical monitoring of complement-targeted therapy. These changes are a result of the growing understanding of the involvement of complement in a diverse set of disorders. To appreciate the importance of proper complement analysis, it is important to understand the role it plays in disease. Historically, it was the absence of complement as manifested in severe infection that was noted. Since then complement has been connected to a variety of inflammatory disorders, such as autoimmune diseases and hereditary angioedema. While the role of complement in the rejection of renal grafts has been known longer, the significant impact of complement. In certain nephropathies has now led to the reclassification of some rare kidney diseases and an increased role for complement analysis in diagnosis. Even more unexpected is that complement has also been implicated in neural, ophtalmological and dermatological disorders. With this level of involvement in some varied and impactful health issues proper complement testing is clearly important; however, analysis of the complement system varies widely among laboratories. Except for a few proteins, such as C3 and C4, there are neither well-characterized standard preparations nor calibrated assays available. This is especially true for the inter-laboratory variation of tests which assess classical, alternative, or lectin pathway function. In addition, there is a need for the standardization of the measurement of complement activation products that are so critical in determining whether clinically relevant complement activation has occurred in vivo. Finally, autoantibodies to complement proteins (e.g. anti-C1q), C3 and C4 convertases (C3 and C4 nephritic factor) or to regulatory proteins

  12. Complement-Mediated Regulation of Metabolism and Basic Cellular Processes.

    Science.gov (United States)

    Hess, Christoph; Kemper, Claudia

    2016-08-16

    Complement is well appreciated as a critical arm of innate immunity. It is required for the removal of invading pathogens and works by directly destroying them through the activation of innate and adaptive immune cells. However, complement activation and function is not confined to the extracellular space but also occurs within cells. Recent work indicates that complement activation regulates key metabolic pathways and thus can impact fundamental cellular processes, such as survival, proliferation, and autophagy. Newly identified functions of complement include a key role in shaping metabolic reprogramming, which underlies T cell effector differentiation, and a role as a nexus for interactions with other effector systems, in particular the inflammasome and Notch transcription-factor networks. This review focuses on the contributions of complement to basic processes of the cell, in particular the integration of complement with cellular metabolism and the potential implications in infection and other disease settings.

  13. Exposure to endocrine disruptor induces transgenerational epigenetic deregulation of microRNAs in primordial germ cells.

    Directory of Open Access Journals (Sweden)

    Miguel A Brieño-Enríquez

    Full Text Available In mammals, germ cell differentiation is initiated in the Primordial Germ Cells (PGCs during fetal development. Prenatal exposure to environmental toxicants such as endocrine disruptors may alter PGC differentiation, development of the male germline and induce transgenerational epigenetic disorders. The anti-androgenic compound vinclozolin represents a paradigmatic example of molecule causing transgenerational effects on germ cells. We performed prenatal exposure to vinclozolin in mice and analyzed the phenotypic and molecular changes in three successive generations. A reduction in the number of embryonic PGCs and increased rate of apoptotic cells along with decrease of fertility rate in adult males were observed in F1 to F3 generations. Blimp1 is a crucial regulator of PGC differentiation. We show that prenatal exposure to vinclozolin deregulates specific microRNAs in PGCs, such as miR-23b and miR-21, inducing disequilibrium in the Lin28/let-7/Blimp1 pathway in three successive generations of males. As determined by global maps of cytosine methylation, we found no evidence for prominent changes in DNA methylation in PGCs or mature sperm. Our data suggest that embryonic exposure to environmental endocrine disruptors induces transgenerational epigenetic deregulation of expression of microRNAs affecting key regulatory pathways of germ cells differentiation.

  14. Binding of Streptococcus pneumoniae endopeptidase O (PepO) to complement component C1q modulates the complement attack and promotes host cell adherence.

    Science.gov (United States)

    Agarwal, Vaibhav; Sroka, Magdalena; Fulde, Marcus; Bergmann, Simone; Riesbeck, Kristian; Blom, Anna M

    2014-05-30

    The Gram-positive species Streptococcus pneumoniae is a human pathogen causing severe local and life-threatening invasive diseases associated with high mortality rates and death. We demonstrated recently that pneumococcal endopeptidase O (PepO) is a ubiquitously expressed, multifunctional plasminogen and fibronectin-binding protein facilitating host cell invasion and evasion of innate immunity. In this study, we found that PepO interacts directly with the complement C1q protein, thereby attenuating the classical complement pathway and facilitating pneumococcal complement escape. PepO binds both free C1q and C1 complex in a dose-dependent manner based on ionic interactions. Our results indicate that recombinant PepO specifically inhibits the classical pathway of complement activation in both hemolytic and complement deposition assays. This inhibition is due to direct interaction of PepO with C1q, leading to a strong activation of the classical complement pathway, and results in consumption of complement components. In addition, PepO binds the classical complement pathway inhibitor C4BP, thereby regulating downstream complement activation. Importantly, pneumococcal surface-exposed PepO-C1q interaction mediates bacterial adherence to host epithelial cells. Taken together, PepO facilitates C1q-mediated bacterial adherence, whereas its localized release consumes complement as a result of its activation following binding of C1q, thus representing an additional mechanism of human complement escape by this versatile pathogen.

  15. Trichinella spiralis Paramyosin Binds Human Complement C1q and Inhibits Classical Complement Activation.

    Directory of Open Access Journals (Sweden)

    Ran Sun

    2015-12-01

    Full Text Available Trichinella spiralis expresses paramyosin (Ts-Pmy as a defense mechanism. Ts-Pmy is a functional protein with binding activity to human complement C8 and C9 and thus plays a role in evading the attack of the host's immune system. In the present study, the binding activity of Ts-Pmy to human complement C1q and its ability to inhibit classical complement activation were investigated.The binding of recombinant and natural Ts-Pmy to human C1q were determined by ELISA, Far Western blotting and immunoprecipitation, respectively. Binding of recombinant Ts-Pmy (rTs-Pmy to C1q inhibited C1q binding to IgM and consequently inhibited C3 deposition. The lysis of antibody-sensitized erythrocytes (EAs elicited by the classical complement pathway was also inhibited in the presence of rTs-Pmy. In addition to inhibiting classical complement activation, rTs-Pmy also suppressed C1q binding to THP-1-derived macrophages, thereby reducing C1q-induced macrophages migration.Our results suggest that T. spiralis paramyosin plays an important role in immune evasion by interfering with complement activation through binding to C1q in addition to C8 and C9.

  16. 补体替代途径中相关因子的激活与年龄相关性黄斑变性的关系%Relationship between some relative factors of the complement alternative pathway and age-related macular degeneration

    Institute of Scientific and Technical Information of China (English)

    葛慧敏; 李芳

    2014-01-01

    年龄相关性黄斑变性( age related macular dengeneration, AMD)是一种与年龄相关的黄斑区退行性病变,最终可导致视力模糊甚至丧失。 AMD的发生受到环境和体内炎症反应综合影响,但其具体发病机制至今仍不清楚,目前研究发现由补体替代途径所介导的炎症反应可能起到关键作用。 C3( complement component 3)、H因子(complement factor H,CFH)、H因子相关蛋白1和3(complement factor H-related 1 and 3,CFHR1 and CFHR3)、B因子(complement factor B,CFB)、I因子(complement factor I,CFI)在替代途径的激活过程中起到了重要的调节作用。CFH可协同由CFI介导的C3 b的裂解过程从而抑制C3转化酶形成,阻滞替代途径的激活。 CFHR1和CFHR3作为CFH竞争性因子与CFH争夺C3 b上的靶位点并可与CFI协同作用影响补体替代途径的激活。 CFB和C3是补体替代途径中的关键因子与AMD中补体替代途径的激活有着密不可分的关系。本文就上述因子的激活在AMD发病过程中的作用进行综述。%Age related macular degeneration ( AMD) is a degenerative disease with the pathological changes in macula lutea and finally leads to the blurred vision even blindness.Environmental and inflammatory reaction may be related with its development.However the exact etiology of the diseases is not clear.AMD is likely a local response of complement alterna-tive pathway which responds to certain systemic inflammatory diseases.Complement component 3 ( C3 ) , complement factor H (CFH), complement factor H-related 1 and 3 (CFHR1 and CFHR3), complement factor B (CFB), and complement factor I ( CFI) are important components in the complement system and also the keys to the pathogenesis of AMD.This re-view is aiming to clarify possible functions of these factors based on recent research.

  17. How antibodies use complement to regulate antibody responses.

    Science.gov (United States)

    Sörman, Anna; Zhang, Lu; Ding, Zhoujie; Heyman, Birgitta

    2014-10-01

    Antibodies, forming immune complexes with their specific antigen, can cause complete suppression or several 100-fold enhancement of the antibody response. Immune complexes containing IgG and IgM may activate complement and in such situations also complement components will be part of the immune complex. Here, we review experimental data on how antibodies via the complement system upregulate specific antibody responses. Current data suggest that murine IgG1, IgG2a, and IgG2b upregulate antibody responses primarily via Fc-receptors and not via complement. In contrast, IgM and IgG3 act via complement and require the presence of complement receptors 1 and 2 (CR1/2) expressed on both B cells and follicular dendritic cells. Complement plays a crucial role for antibody responses not only to antigen complexed to antibodies, but also to antigen administered alone. Lack of C1q, but not of Factor B or MBL, severely impairs antibody responses suggesting involvement of the classical pathway. In spite of this, normal antibody responses are found in mice lacking several activators of the classical pathway (complement activating natural IgM, serum amyloid P component (SAP), specific intracellular adhesion molecule-grabbing non-integrin R1 (SIGN-R1) or C-reactive protein. Possible explanations to these observations will be discussed.

  18. Complement activation promotes muscle inflammation during modified muscle use

    Science.gov (United States)

    Frenette, J.; Cai, B.; Tidball, J. G.

    2000-01-01

    Modified muscle use can result in muscle inflammation that is triggered by unidentified events. In the present investigation, we tested whether the activation of the complement system is a component of muscle inflammation that results from changes in muscle loading. Modified rat hindlimb muscle loading was achieved by removing weight-bearing from the hindlimbs for 10 days followed by reloading through normal ambulation. Experimental animals were injected with the recombinant, soluble complement receptor sCR1 to inhibit complement activation. Assays for complement C4 or factor B in sera showed that sCR1 produced large reductions in the capacity for activation of the complement system through both the classical and alternative pathways. Analysis of complement C4 concentration in serum in untreated animals showed that the classical pathway was activated during the first 2 hours of reloading. Analysis of factor B concentration in untreated animals showed activation of the alternative pathway at 6 hours of reloading. Administration of sCR1 significantly attenuated the invasion of neutrophils (-49%) and ED1(+) macrophages (-52%) that occurred in nontreated animals after 6 hours of reloading. The presence of sCR1 also reduced significantly the degree of edema by 22% as compared to untreated animals. Together, these data show that increased muscle loading activated the complement system which then briefly contributes to the early recruitment of inflammatory cells during modified muscle loading.

  19. Complement-dependent transport of antigen into B cell follicles

    DEFF Research Database (Denmark)

    Gonzalez, Santiago F.; Lukacs-Kornek, Veronika; Kuligowski, Michael P.

    2010-01-01

    an additional novel pathway in which complement C3 and its receptors enhance humoral immunity through delivery of Ag to the B cell compartment. In this review, we discuss this pathway and highlight several novel exceptions recently found with a model influenza vaccine, such as mannose-binding lectin...

  20. Deregulated microRNAs in multiple myeloma.

    Science.gov (United States)

    Benetatos, Leonidas; Vartholomatos, George

    2012-02-15

    MicroRNAs are short noncoding RNAS involved in gene expression regulation under physiological and pathological situations. They bind to mRNA of target genes and are potential regulators of gene expression at a post-transcription level through the RNA interference pathway. They are estimated to represent 1% to 2% of the known eukaryotic genome, and it has been demonstrated that they are involved in the pathogenesis of neurodegenerative diseases, cancer, metabolism disorders, and heart disease. MicroRNAs are known to act as tumor suppressors or oncogenes in cancer biology. The authors describe the current knowledge on microRNA involvement in regulatory pathways that characterize multiple myeloma pathogenesis gained from in vitro and in vivo studies. These small molecules interact with important factors such as p53, SOCS1, IGF-1, IGF-1R, vascular endothelial growth factor, NF-κB, and others. As such, microRNAs represent an attractive therapeutic target in the context of multiple myeloma interfering with the myeloma regulatory networks. Further studies are needed to better understand their role in myelomagenesis and their therapeutic potential.

  1. Complement and Antibody-Mediated Enhancement of Erythrocyte Invasion by Plasmodium Falciparum

    Science.gov (United States)

    2016-04-01

    complement pathway involved in study the effect of different complement deficiencies by infecting genetically modified mice that are deficient in...Ouyang, X., et al., 2007. Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal

  2. Peptide Inhibitor of Complement C1 (PIC1 Rapidly Inhibits Complement Activation after Intravascular Injection in Rats.

    Directory of Open Access Journals (Sweden)

    Julia A Sharp

    Full Text Available The complement system has been increasingly recognized to play a pivotal role in a variety of inflammatory and autoimmune diseases. Consequently, therapeutic modulators of the classical, lectin and alternative pathways of the complement system are currently in pre-clinical and clinical development. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement and is referred to as Peptide Inhibitor of Complement C1 (PIC1. In this study, we determined that the lead PIC1 variant demonstrates a salt-dependent binding to C1q, the initiator molecule of the classical pathway. Additionally, this peptide bound to the lectin pathway initiator molecule MBL as well as the ficolins H, M and L, suggesting a common mechanism of PIC1 inhibitory activity occurs via binding to the collagen-like tails of these collectin molecules. We further analyzed the effect of arginine and glutamic acid residue substitution on the complement inhibitory activity of our lead derivative in a hemolytic assay and found that the original sequence demonstrated superior inhibitory activity. To improve upon the solubility of the lead derivative, a pegylated, water soluble variant was developed, structurally characterized and demonstrated to inhibit complement activation in mouse plasma, as well as rat, non-human primate and human serum in vitro. After intravenous injection in rats, the pegylated derivative inhibited complement activation in the blood by 90% after 30 seconds, demonstrating extremely rapid function. Additionally, no adverse toxicological effects were observed in limited testing. Together these results show that PIC1 rapidly inhibits classical complement activation in vitro and in vivo and is functional for a variety of animal species, suggesting its utility in animal models of classical complement-mediated diseases.

  3. Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.

    Science.gov (United States)

    Mathieu, Véronique; Pirker, Christine; Schmidt, Wolfgang M; Spiegl-Kreinecker, Sabine; Lötsch, Daniela; Heffeter, Petra; Hegedus, Balazs; Grusch, Michael; Kiss, Robert; Berger, Walter

    2012-04-01

    Melanoma is a devastating skin cancer characterized by distinct biological subtypes. Besides frequent mutations in growth- and survival-promoting genes like BRAF and NRAS, melanomas additionally harbor complex non-random genomic alterations. Using an integrative approach, we have analysed genomic and gene expression changes in human melanoma cell lines (N=32) derived from primary tumors and various metastatic sites and investigated the relation to local growth aggressiveness as xenografts in immuno-compromised mice (N=22). Although the vast majority >90% of melanoma models harbored mutations in either BRAF or NRAS, significant differences in subcutaneous growth aggressiveness became obvious. Unsupervised clustering revealed that genomic alterations rather than gene expression data reflected this aggressive phenotype, while no association with histology, stage or metastatic site of the original melanoma was found. Genomic clustering allowed separation of melanoma models into two subgroups with differing local growth aggressiveness in vivo. Regarding genes expressed at significantly altered levels between these subgroups, a surprising correlation with the respective gene doses (>85% accordance) was found. Genes deregulated at the DNA and mRNA level included well-known cancer genes partly already linked to melanoma (RAS genes, PTEN, AURKA, MAPK inhibitors Sprouty/Spred), but also novel candidates like SIPA1 (a Rap1GAP). Pathway mining further supported deregulation of Rap1 signaling in the aggressive subgroup e.g. by additional repression of two Rap1GEFs. Accordingly, siRNA-mediated down-regulation of SIPA1 exerted significant effects on clonogenicity, adherence and migration in aggressive melanoma models. Together our data suggest that an aneuploidy-driven gene expression deregulation drives local aggressiveness in human melanoma.

  4. miRNA-mediated deregulation in leukemia

    Directory of Open Access Journals (Sweden)

    Carmela eDell'Aversana

    2012-11-01

    Full Text Available MicroRNAs (miRNAs are small non-coding RNAs 18 to 22 nucleotides (nt long able to fine-tune post-transcriptional gene expression. Extensive investigation intobiogenesis, mechanism of action and functions of miRNAs has clearly revealed their prompt control in developmental timing, differentiation, proliferation, cell death and metabolism. Deregulationof miRNA-mediated pathways may contribute to pathological conditions such as tumors, including hematological cancer, thus suggesting that miRNAs act both as tumor-suppressor genes (TSG and oncogenes (OG.Here, we provide an overview of the current understanding of the aberration of miRNA biogenesis, activity and post-transcriptional control in leukemogenesis.

  5. Understanding electricity market reforms and the case of Philippine deregulation

    Energy Technology Data Exchange (ETDEWEB)

    Santiago, Andrea; Roxas, Fernando

    2010-03-15

    The experience of the Philippines offers lessons that should be relevant to any country seeking to deregulate its power industry. Regardless of structure, consumers must face the real price of electricity production and delivery that is closer to marginal cost. Politically motivated prices merely shift the burden from ratepayers to taxpayers. And any reform should work within a reasonable timetable. (author)

  6. Adaptive Game-based Agent Negotiation in Deregulated Energy Markets

    NARCIS (Netherlands)

    Capodieci, Nicola; Cabri, Giacomo; Pagani, Giuliano Andrea; Aiello, Marco

    2012-01-01

    In the emerging deregulated energy paradigm enabled by the Smart Grid, energy provisioning will change drastically. Energy contracts will be negotiated between a potential multitude of parties at high frequency (e.g., several times per day) based on local needs and micro-generation production facili

  7. Teacher Education Policy in Canada: Beyond Professionalization and Deregulation

    Science.gov (United States)

    Walker, Judith; von Bergmann, HsingChi

    2013-01-01

    This paper empirically investigates Grimmett's (2008, 2009) thesis that recent Canadian teacher education policy is best characterized by dual forces of deregulation and professionalization resulting from a neoliberal policy environment. Specifically, we examine teacher education governance, policy reform, and political context from 2000 to 2010,…

  8. Vulnerable Consumers in the Deregulated Dutch Health System

    NARCIS (Netherlands)

    Booltink, L.; Genugten, M.L. van; Lako, C.J.

    2015-01-01

    Public service deregulation is favoured for motivating providers to offer consumers better price-quality services. Consequently, consumers are enabled to make informed choices and choose for the best service provider. However, recent publications reveal that consumers are not capable of exercising o

  9. University Staff's Perception of Deregulation on Higher Education in Nigeria

    Science.gov (United States)

    Adebayo, Florence Aduke

    2014-01-01

    The study investigated the university staff's perception on deregulation of higher education in Nigeria. Descriptive research of the survey type was used for the study. The population comprised all the university staff of universities in Ekiti and Ondo states, Nigeria. Simple random sampling technique was used to select 700 academic and…

  10. Teacher Education Policy in Canada: Beyond Professionalization and Deregulation

    Science.gov (United States)

    Walker, Judith; von Bergmann, HsingChi

    2013-01-01

    This paper empirically investigates Grimmett's (2008, 2009) thesis that recent Canadian teacher education policy is best characterized by dual forces of deregulation and professionalization resulting from a neoliberal policy environment. Specifically, we examine teacher education governance, policy reform, and political context from 2000 to 2010,…

  11. Complement system in lung disease.

    Science.gov (United States)

    Pandya, Pankita H; Wilkes, David S

    2014-10-01

    In addition to its established contribution to innate immunity, recent studies have suggested novel roles for the complement system in the development of various lung diseases. Several studies have demonstrated that complement may serve as a key link between innate and adaptive immunity in a variety of pulmonary conditions. However, the specific contributions of complement to lung diseases based on innate and adaptive immunity are just beginning to emerge. Elucidating the role of complement-mediated immune regulation in these diseases will help to identify new targets for therapeutic interventions.

  12. Complement-Coagulation Cross-Talk: A Potential Mediator of the Physiological Activation of Complement by Low pH.

    Science.gov (United States)

    Kenawy, Hany Ibrahim; Boral, Ismet; Bevington, Alan

    2015-01-01

    The complement system is a major constituent of the innate immune system. It not only bridges innate and adaptive arms of the immune system but also links the immune system with the coagulation system. Current understanding of the role of complement has extended far beyond fighting of infections, and now encompasses maintenance of homeostasis, tissue regeneration, and pathophysiology of multiple diseases. It has been known for many years that complement activation is strongly pH sensitive, but only relatively recently has the physiological significance of this been appreciated. Most complement assays are carried out at the physiological pH 7.4. However, pH in some extracellular compartments, for example, renal tubular fluid in parts of the tubule, and extracellular fluid at inflammation loci, is sufficiently acidic to activate complement. The exact molecular mechanism of this activation is still unclear, but possible cross-talk between the contact system (intrinsic pathway) and complement may exist at low pH with subsequent complement activation. The current article reviews the published data on the effect of pH on the contact system and complement activity, the nature of the pH sensor molecules, and the clinical implications of these effects. Of particular interest is chronic kidney disease (CKD) accompanied by metabolic acidosis, in which therapeutic alkalinization of urine has been shown significantly to reduce tubular complement activation products, an effect, which may have important implications for slowing progression of CKD.

  13. Complement and membrane-bound complement regulatory proteins as biomarkers and therapeutic targets for autoimmune inflammatory disorders, RA and SLE.

    Science.gov (United States)

    Das, Nibhriti

    2015-11-01

    Complement system is a major effecter system of the innate immunity that bridges with adaptive immunity. The system consists of about 40 humoral and cell surface proteins that include zymogens, receptors and regulators. The zymogens get activated in a cascade fashion by antigen-antibody complex, antigen alone or by polymannans, respectively, by the classical, alternative and mannose binding lectin (MBL) pathways. The ongoing research on complement regulators and complement receptors suggest key role of these proteins in the initiation, regulation and effecter mechanisms of the innate and adaptive immunity. Although, the complement system provides the first line of defence against the invading pathogens, its aberrant uncontrolled activation causes extensive self tissue injury. A large number of humoral and cell surface complement regulatory protein keep the system well-regulated in healthy individuals. Complement profiling had brought important information on the pathophysiology of several infectious and chronic inflammatory disorders. In view of the diversity of the clinical disorders involving abnormal complement activity or regulation, which include both acute and chronic diseases that affect a wide range of organs, diverse yet specifically tailored therapeutic approaches may be needed to shift complement back into balance. This brief review discusses on the complement system, its functions and its importance as biomarkers and therapeutic targets for autoimmune diseases with focus on SLE and RA.

  14. Keeping It All Going-Complement Meets Metabolism.

    Science.gov (United States)

    Kolev, Martin; Kemper, Claudia

    2017-01-01

    The complement system is an evolutionary old and crucial component of innate immunity, which is key to the detection and removal of invading pathogens. It was initially discovered as a liver-derived sentinel system circulating in serum, the lymph, and interstitial fluids that mediate the opsonization and lytic killing of bacteria, fungi, and viruses and the initiation of the general inflammatory responses. Although work performed specifically in the last five decades identified complement also as a critical instructor of adaptive immunity-indicating that complement's function is likely broader than initially anticipated-the dominant opinion among researchers and clinicians was that the key complement functions were in principle defined. However, there is now a growing realization that complement activity goes well beyond "classic" immune functions and that this system is also required for normal (neuronal) development and activity and general cell and tissue integrity and homeostasis. Furthermore, the recent discovery that complement activation is not confined to the extracellular space but occurs within cells led to the surprising understanding that complement is involved in the regulation of basic processes of the cell, particularly those of metabolic nature-mostly via novel crosstalks between complement and intracellular sensor, and effector, pathways that had been overlooked because of their spatial separation. These paradigm shifts in the field led to a renaissance in complement research and provide new platforms to now better understand the molecular pathways underlying the wide-reaching effects of complement functions in immunity and beyond. In this review, we will cover the current knowledge about complement's emerging relationship with the cellular metabolism machinery with a focus on the functional differences between serum-circulating versus intracellularly active complement during normal cell survival and induction of effector functions. We will also

  15. The complement system in ischemia-reperfusion injuries.

    Science.gov (United States)

    Gorsuch, William B; Chrysanthou, Elvina; Schwaeble, Wilhelm J; Stahl, Gregory L

    2012-11-01

    Tissue injury and inflammation following ischemia and reperfusion of various organs have been recognized for many years. Many reviews have been written over the last several decades outlining the role of complement in ischemia/reperfusion injury. This short review provides a current state of the art knowledge on the complement pathways activated, complement components involved and a review of the clinical biologics/inhibitors used in the clinical setting of ischemia/reperfusion. This is not a complete review of the complement system in ischemia and reperfusion injury but will give the reader an updated view point of the field, potential clinical use of complement inhibitors, and the future studies needed to advance the field.

  16. 75 FR 68321 - Forage Genetics International; Supplemental Request for Partial Deregulation of Roundup Ready...

    Science.gov (United States)

    2010-11-05

    ... Animal and Plant Health Inspection Service Forage Genetics International; Supplemental Request for... ``partial deregulation'' from Forage Genetics International for the planting, harvesting, and movement... submitted to the Agency from Forage Genetics International requesting a ``partial deregulation.'' ADDRESSES...

  17. Systemic complement activation in age-related macular degeneration.

    Science.gov (United States)

    Scholl, Hendrik P N; Charbel Issa, Peter; Walier, Maja; Janzer, Stefanie; Pollok-Kopp, Beatrix; Börncke, Florian; Fritsche, Lars G; Chong, Ngaihang V; Fimmers, Rolf; Wienker, Thomas; Holz, Frank G; Weber, Bernhard H F; Oppermann, Martin

    2008-07-02

    Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (pAMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility.

  18. Systemic complement activation in age-related macular degeneration.

    Directory of Open Access Journals (Sweden)

    Hendrik P N Scholl

    Full Text Available Dysregulation of the alternative pathway (AP of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD, the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112 and controls (n = 67. Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH, factor B-C2 (BF-C2 and complement C3 (C3 genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001, were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility.

  19. Transcriptome and small RNA deep sequencing reveals deregulation of miRNA biogenesis in human glioma.

    Science.gov (United States)

    Moore, Lynette M; Kivinen, Virpi; Liu, Yuexin; Annala, Matti; Cogdell, David; Liu, Xiuping; Liu, Chang-Gong; Sawaya, Raymond; Yli-Harja, Olli; Shmulevich, Ilya; Fuller, Gregory N; Zhang, Wei; Nykter, Matti

    2013-02-01

    Altered expression of oncogenic and tumour-suppressing microRNAs (miRNAs) is widely associated with tumourigenesis. However, the regulatory mechanisms underlying these alterations are poorly understood. We sought to shed light on the deregulation of miRNA biogenesis promoting the aberrant miRNA expression profiles identified in these tumours. Using sequencing technology to perform both whole-transcriptome and small RNA sequencing of glioma patient samples, we examined precursor and mature miRNAs to directly evaluate the miRNA maturation process, and examined expression profiles for genes involved in the major steps of miRNA biogenesis. We found that ratios of mature to precursor forms of a large number of miRNAs increased with the progression from normal brain to low-grade and then to high-grade gliomas. The expression levels of genes involved in each of the three major steps of miRNA biogenesis (nuclear processing, nucleo-cytoplasmic transport, and cytoplasmic processing) were systematically altered in glioma tissues. Survival analysis of an independent data set demonstrated that the alteration of genes involved in miRNA maturation correlates with survival in glioma patients. Direct quantification of miRNA maturation with deep sequencing demonstrated that deregulation of the miRNA biogenesis pathway is a hallmark for glioma genesis and progression.

  20. Complement receptor 2-mediated targeting of complement inhibitors to sites of complement activation.

    Science.gov (United States)

    Song, Hongbin; He, Chun; Knaak, Christian; Guthridge, Joel M; Holers, V Michael; Tomlinson, Stephen

    2003-06-01

    In a strategy to specifically target complement inhibitors to sites of complement activation and disease, recombinant fusion proteins consisting of a complement inhibitor linked to a C3 binding region of complement receptor (CR) 2 were prepared and characterized. Natural ligands for CR2 are C3 breakdown products deposited at sites of complement activation. Fusion proteins were prepared consisting of a human CR2 fragment linked to either the N terminus or C terminus of soluble forms of the membrane complement inhibitors decay accelerating factor (DAF) or CD59. The targeted complement inhibitors bound to C3-opsonized cells, and all were significantly more effective (up to 20-fold) than corresponding untargeted inhibitors at protecting target cells from complement. CR2 fusion proteins also inhibited CR3-dependent adhesion of U937 cells to C3 opsonized erythrocytes, indicating a second potential anti-inflammatory mechanism of CR2 fusion proteins, since CR3 is involved in endothelial adhesion and diapedesis of leukocytes at inflammatory sites. Finally, the in vivo validity of the targeting strategy was confirmed by the demonstration that CR2-DAF, but not soluble DAF, targets to the kidney in mouse models of lupus nephritis that are associated with renal complement deposition.

  1. The complement cascade in kidney disease: from sideline to center stage.

    Science.gov (United States)

    McCaughan, Jennifer A; O'Rourke, Declan M; Courtney, Aisling E

    2013-09-01

    Activation of the complement pathway is implicated in the pathogenesis of many kidney diseases. The pathologic and clinical features of these diseases are determined in part by the mechanism and location of complement activation within the kidney parenchyma. This review describes the physiology, action, and control of the complement cascade and explains the role of complement overactivation and dysregulation in kidney disease. There have been recent advances in the understanding of the effects of upregulation of the complement cascade after kidney transplantation. Complement plays an important role in initiating and propagating damage to transplanted kidneys in ischemia-reperfusion injury, antibody-mediated rejection, and cell-mediated rejection. Complement-targeting therapies presently are in development, and the first direct complement medication for kidney disease was licensed in 2011. The potential therapeutic targets for anticomplement drugs in kidney disease are described. Clinical and experimental studies are ongoing to identify further roles for complement-targeting therapy.

  2. Complement evasion by Staphylococcus aureus

    NARCIS (Netherlands)

    Jongerius, I.

    2010-01-01

    The complement system is the first line of defense against invading microorganisms. Activation of the complement system results in the coverage of bacteria with C3b, resulting in phagocytosis, and formation of C5a which is important for chemotaxis of neutrophils towards the site of infection. Staphy

  3. Complement's participation in acquired immunity

    DEFF Research Database (Denmark)

    Nielsen, Claus Henrik; Leslie, Robert Graham Quinton

    2002-01-01

    in which antigen is seen, be it alone or in association with natural or induced antibodies and/or C3-complement fragments. The aim of this review is to describe the present status of our understanding of complement's participation in acquired immunity and the regulation of autoimmune responses....

  4. Phospholipase C isozymes are deregulated in colorectal cancer--insights gained from gene set enrichment analysis of the transcriptome.

    Directory of Open Access Journals (Sweden)

    Stine A Danielsen

    Full Text Available Colorectal cancer (CRC is one of the most common cancer types in developed countries. To identify molecular networks and biological processes that are deregulated in CRC compared to normal colonic mucosa, we applied Gene Set Enrichment Analysis to two independent transcriptome datasets, including a total of 137 CRC and ten normal colonic mucosa samples. Eighty-two gene sets as described by the Kyoto Encyclopedia of Genes and Genomes database had significantly altered gene expression in both datasets. These included networks associated with cell division, DNA maintenance, and metabolism. Among signaling pathways with known changes in key genes, the "Phosphatidylinositol signaling network", comprising part of the PI3K pathway, was found deregulated. The downregulated genes in this pathway included several members of the Phospholipase C protein family, and the reduced expression of two of these, PLCD1 and PLCE1, were successfully validated in CRC biopsies (n = 70 and cell lines (n = 19 by quantitative analyses. The repression of both genes was found associated with KRAS mutations (P = 0.005 and 0.006, respectively, and we observed that microsatellite stable carcinomas with reduced PLCD1 expression more frequently had TP53 mutations (P = 0.002. Promoter methylation analyses of PLCD1 and PLCE1 performed in cell lines and tumor biopsies revealed that methylation of PLCD1 can contribute to reduced expression in 40% of the microsatellite instable carcinomas. In conclusion, we have identified significantly deregulated pathways in CRC, and validated repression of PLCD1 and PLCE1 expression. This illustrates that the GSEA approach may guide discovery of novel biomarkers in cancer.

  5. Complement in health and disease.

    Science.gov (United States)

    Carroll, Maria V; Sim, Robert B

    2011-09-16

    The complement system consists of about 35-40 proteins and glycoproteins present in blood plasma or on cell surfaces. Its main biological function is to recognise "foreign" particles and macromolecules, and to promote their elimination either by opsonisation or lysis. Although historically complement has been studied as a system for immune defence against bacteria, it has an important homeostatic role in which it recognises damaged or altered "self" components. Thus complement has major roles in both immune defence against microorganisms, and in clearance of damaged or "used" host components. Since complement proteins opsonise or lyse cells, complement can damage healthy host cells and tissues. The system is regulated by many endogenous regulatory proteins. Regulation is sometimes imperfect and both too much and too little complement activation is associated with many diseases. Excessive or inappropriate activation can cause tissue damage in diseases such as rheumatoid arthritis, age-related macular degeneration (AMD), multiple sclerosis, ischemia-reperfusion injury (e.g. ischemic stroke). Insufficient complement activity is associated with susceptibility to infection (mainly bacterial) and development of autoimmune disease, like SLE (systemic lupus erythematosus).

  6. IDENTIFICATION OF HARMONIC SOURCES IN DEREGULATED POWER SECTOR

    Directory of Open Access Journals (Sweden)

    KRITI VAID,

    2011-03-01

    Full Text Available In this paper identification of origin of harmonic source in deregulated power sector has been carried out. Critical impedance method (CIM for detection of harmonic disturbances caused between utility and source side has already been reported in literature. The method is based on direction of reactive power flow in the power system when there is the presence of harmonic load. Taking the CIM as the base method harmonic sources are identified in deregulated power sector. Due to unavailability of practical data simulation approach has been adopted. A five bus system model with two Generation ompanies (GENCOS has been simulated for power transfer from GENCO to the considered five bus system. Harmonic current is injected into the system by using a three phase diode rectifier. The results obtainedusing the CIM clearly identifies whether the harmonic source is present in GENCO side or the load side.

  7. BANKING DEREGULATION AND FINANCIAL STABILITY IN EMERGING MARKET ECONOMIES

    Directory of Open Access Journals (Sweden)

    Adnen CHOCKRI

    2011-12-01

    Full Text Available Since the 80’s, an increasing number of emergent countries have begun in the process of banking deregulation. This policy of liberalization of the financial systems was stimulated by the increase of the national debts and the inconsistency of the restrictions with the new economic and financial world. However, these last decades were marked by great financial crises which became world extensive. From there arose the question whether the process of deregulation, started by the developed countries since the sixties and accentuated in the eighties by the emergent and developing countries, contributed to the recent crises. Several theoretical and empirical studies investigated this question to show that these crises concern various fields: macroeconomic imbalances, structural weakness of the financial systems, instability of international flows of capital, etc.

  8. An Oncogenic Role for Alternative NF-κB Signaling in DLBCL Revealed upon Deregulated BCL6 Expression

    Directory of Open Access Journals (Sweden)

    Baochun Zhang

    2015-05-01

    Full Text Available Diffuse large B cell lymphoma (DLBCL is a complex disease comprising diverse subtypes and genetic profiles. Possibly because of the prevalence of genetic alterations activating canonical NF-κB activity, a role for oncogenic lesions that activate the alternative NF-κB pathway in DLBCL has remained elusive. Here, we show that deletion/mutation of TRAF3, a negative regulator of the alternative NF-κB pathway, occurs in ∼15% of DLBCLs and that it often coexists with BCL6 translocation, which prevents terminal B cell differentiation. Accordingly, in a mouse model constitutive activation of the alternative NF-κB pathway cooperates with BCL6 deregulation in DLBCL development. This work demonstrates a key oncogenic role for the alternative NF-κB pathway in DLBCL development.

  9. Managing an evolution: Deregulation of the electric utility industry

    Energy Technology Data Exchange (ETDEWEB)

    Skinner, S.K.

    1994-12-31

    The author discusses the emerging competitive situation in the electric power industry as deregulation of electric utilities looms on the horizon. The paper supports this change, and the competition it will bring, but urges caution as changes are instituted, and the regulatory bodies decide how and how much to free, and at what rates. The reason for his urge for caution comes from historical experience of other industries, which were smaller and had less direct impact on every American.

  10. Vulnerable Consumers in the Deregulated Dutch Health System

    OpenAIRE

    Booltink, L.; Genugten, M.L. van; Lako, C.J.

    2015-01-01

    Public service deregulation is favoured for motivating providers to offer consumers better price-quality services. Consequently, consumers are enabled to make informed choices and choose for the best service provider. However, recent publications reveal that consumers are not capable of exercising optimal choice behaviour. Despite these concerns, evidence is lacking on the extent to which potentially vulnerable consumers make use of the core element of deregulation—switching health plans. Thi...

  11. Generation capacity expansion planning in deregulated electricity markets

    Science.gov (United States)

    Sharma, Deepak

    With increasing demand of electric power in the context of deregulated electricity markets, a good strategic planning for the growth of the power system is critical for our tomorrow. There is a need to build new resources in the form of generation plants and transmission lines while considering the effects of these new resources on power system operations, market economics and the long-term dynamics of the economy. In deregulation, the exercise of generation planning has undergone a paradigm shift. The first stage of generation planning is now undertaken by the individual investors. These investors see investments in generation capacity as an increasing business opportunity because of the increasing market prices. Therefore, the main objective of such a planning exercise, carried out by individual investors, is typically that of long-term profit maximization. This thesis presents some modeling frameworks for generation capacity expansion planning applicable to independent investor firms in the context of power industry deregulation. These modeling frameworks include various technical and financing issues within the process of power system planning. The proposed modeling frameworks consider the long-term decision making process of investor firms, the discrete nature of generation capacity addition and incorporates transmission network modeling. Studies have been carried out to examine the impact of the optimal investment plans on transmission network loadings in the long-run by integrating the generation capacity expansion planning framework within a modified IEEE 30-bus transmission system network. The work assesses the importance of arriving at an optimal IRR at which the firm's profit maximization objective attains an extremum value. The mathematical model is further improved to incorporate binary variables while considering discrete unit sizes, and subsequently to include the detailed transmission network representation. The proposed models are novel in the

  12. Complement-dependent transport of antigen into B cell follicles

    DEFF Research Database (Denmark)

    Gonzalez, Santiago F.; Lukacs-Kornek, Veronika; Kuligowski, Michael P.

    2010-01-01

    Since the original proposal by Fearon and Locksley (Fearon and Locksley. 1996. Science 272: 50-53) that the complement system linked innate and adaptive immunity, there has been a rapid expansion of studies on this topic. With the advance of intravital imaging, a number of recent papers revealed...... an additional novel pathway in which complement C3 and its receptors enhance humoral immunity through delivery of Ag to the B cell compartment. In this review, we discuss this pathway and highlight several novel exceptions recently found with a model influenza vaccine, such as mannose-binding lectin...

  13. Interpain A, a cysteine proteinase from Prevotella intermedia, inhibits complement by degrading complement factor C3.

    Directory of Open Access Journals (Sweden)

    Michal Potempa

    2009-02-01

    Full Text Available Periodontitis is an inflammatory disease of the supporting structures of the teeth caused by, among other pathogens, Prevotella intermedia. Many strains of P. intermedia are resistant to killing by the human complement system, which is present at up to 70% of serum concentration in gingival crevicular fluid. Incubation of human serum with recombinant cysteine protease of P. intermedia (interpain A resulted in a drastic decrease in bactericidal activity of the serum. Furthermore, a clinical strain 59 expressing interpain A was more serum-resistant than another clinical strain 57, which did not express interpain A, as determined by Western blotting. Moreover, in the presence of the cysteine protease inhibitor E64, the killing of strain 59 by human serum was enhanced. Importantly, we found that the majority of P. intermedia strains isolated from chronic and aggressive periodontitis carry and express the interpain A gene. The protective effect of interpain A against serum bactericidal activity was found to be attributable to its ability to inhibit all three complement pathways through the efficient degradation of the alpha-chain of C3 -- the major complement factor common to all three pathways. P. intermedia has been known to co-aggregate with P. gingivalis, which produce gingipains to efficiently degrade complement factors. Here, interpain A was found to have a synergistic effect with gingipains on complement degradation. In addition, interpain A was able to activate the C1 complex in serum, causing deposition of C1q on inert and bacterial surfaces, which may be important at initial stages of infection when local inflammatory reaction may be beneficial for a pathogen. Taken together, the newly characterized interpain A proteinase appears to be an important virulence factor of P. intermedia.

  14. Current Understanding of the Role of Complement in IgA Nephropathy

    Science.gov (United States)

    Maillard, Nicolas; Wyatt, Robert J.; Julian, Bruce A.; Kiryluk, Krzysztof; Gharavi, Ali; Fremeaux-Bacchi, Veronique

    2015-01-01

    Complement activation has a role in the pathogenesis of IgA nephropathy, an autoimmune disease mediated by pathogenic immune complexes consisting of galactose-deficient IgA1 bound by antiglycan antibodies. Of three complement-activation pathways, the alternative and lectin pathways are involved in IgA nephropathy. IgA1 can activate both pathways in vitro, and pathway components are present in the mesangial immunodeposits, including properdin and factor H in the alternative pathway and mannan-binding lectin, mannan–binding lectin–associated serine proteases 1 and 2, and C4d in the lectin pathway. Genome–wide association studies identified deletion of complement factor H–related genes 1 and 3 as protective against the disease. Because the corresponding gene products compete with factor H in the regulation of the alternative pathway, it has been hypothesized that the absence of these genes could lead to more potent inhibition of complement by factor H. Complement activation can take place directly on IgA1–containing immune complexes in circulation and/or after their deposition in the mesangium. Notably, complement factors and their fragments may serve as biomarkers of IgA nephropathy in serum, urine, or renal tissue. A better understanding of the role of complement in IgA nephropathy may provide potential targets and rationale for development of complement-targeting therapy of the disease. PMID:25694468

  15. Multiobjective Optimization Methods for Congestion Management in Deregulated Power Systems

    Directory of Open Access Journals (Sweden)

    K. Vijayakumar

    2012-01-01

    Full Text Available Congestion management is one of the important functions performed by system operator in deregulated electricity market to ensure secure operation of transmission system. This paper proposes two effective methods for transmission congestion alleviation in deregulated power system. Congestion or overload in transmission networks is alleviated by rescheduling of generators and/or load shedding. The two objectives conflicting in nature (1 transmission line over load and (2 congestion cost are optimized in this paper. The multiobjective fuzzy evolutionary programming (FEP and nondominated sorting genetic algorithm II methods are used to solve this problem. FEP uses the combined advantages of fuzzy and evolutionary programming (EP techniques and gives better unique solution satisfying both objectives, whereas nondominated sorting genetic algorithm (NSGA II gives a set of Pareto-optimal solutions. The methods propose an efficient and reliable algorithm for line overload alleviation due to critical line outages in a deregulated power markets. The quality and usefulness of the algorithm is tested on IEEE 30 bus system.

  16. Recurrently deregulated lncRNAs in hepatocellular carcinoma

    Science.gov (United States)

    Yang, Yang; Chen, Lei; Gu, Jin; Zhang, Hanshuo; Yuan, Jiapei; Lian, Qiuyu; Lv, Guishuai; Wang, Siqi; Wu, Yang; Yang, Yu-Cheng T.; Wang, Dongfang; Liu, Yang; Tang, Jing; Luo, Guijuan; Li, Yang; Hu, Long; Sun, Xinbao; Wang, Dong; Guo, Mingzhou; Xi, Qiaoran; Xi, Jianzhong; Wang, Hongyang; Zhang, Michael Q.; Lu, Zhi John

    2017-01-01

    Hepatocellular carcinoma (HCC) cells often invade the portal venous system and subsequently develop into portal vein tumour thrombosis (PVTT). Long noncoding RNAs (lncRNAs) have been associated with HCC, but a comprehensive analysis of their specific association with HCC metastasis has not been conducted. Here, by analysing 60 clinical samples' RNA-seq data from 20 HCC patients, we have identified and characterized 8,603 candidate lncRNAs. The expression patterns of 917 recurrently deregulated lncRNAs are correlated with clinical data in a TCGA cohort and published liver cancer data. Matched array data from the 60 samples show that copy number variations (CNVs) and alterations in DNA methylation contribute to the observed recurrent deregulation of 235 lncRNAs. Many recurrently deregulated lncRNAs are enriched in co-expressed clusters of genes related to cell adhesion, immune response and metabolic processes. Candidate lncRNAs related to metastasis, such as HAND2-AS1, were further validated using RNAi-based loss-of-function assays. Thus, we provide a valuable resource of functional lncRNAs and biomarkers associated with HCC tumorigenesis and metastasis. PMID:28194035

  17. DEK Expression is controlled by E2F and deregulated in diverse tumor types.

    Science.gov (United States)

    Carro, Maria Stella; Spiga, Fabio Mario; Quarto, Micaela; Di Ninni, Valentina; Volorio, Sara; Alcalay, Myriam; Müller, Heiko

    2006-06-01

    Deregulation of the retinoblastoma (pRB) tumor suppressor pathway associated with aberrant activity of E2F transcription factors is frequently observed in human cancer. Microarray based analyses have revealed a large number of potential downstream mediators of the tumor suppressing activity of pRB, including DEK, a fusion partner of CAN found in a subset of acute myeloid leukaemia (AML) patients carrying a (6; 9) translocation. Here we report that the expression of DEK is under direct control of E2F transcription factors. Chromatin immunoprecipitation assays show that the DEK promoter is bound by endogenous E2F in vivo. The DEK promoter is transactivated by E2F and mutation of E2F binding sites eliminates this effect. Expression levels of DEK in human tumors have been investigated by tissue micro array analysis. We find that DEK is overexpressed in many solid tumors such as colon cancer, larynx cancer, bladder cancer, and melanoma.

  18. Keeping It All Going—Complement Meets Metabolism

    Science.gov (United States)

    Kolev, Martin; Kemper, Claudia

    2017-01-01

    The complement system is an evolutionary old and crucial component of innate immunity, which is key to the detection and removal of invading pathogens. It was initially discovered as a liver-derived sentinel system circulating in serum, the lymph, and interstitial fluids that mediate the opsonization and lytic killing of bacteria, fungi, and viruses and the initiation of the general inflammatory responses. Although work performed specifically in the last five decades identified complement also as a critical instructor of adaptive immunity—indicating that complement’s function is likely broader than initially anticipated—the dominant opinion among researchers and clinicians was that the key complement functions were in principle defined. However, there is now a growing realization that complement activity goes well beyond “classic” immune functions and that this system is also required for normal (neuronal) development and activity and general cell and tissue integrity and homeostasis. Furthermore, the recent discovery that complement activation is not confined to the extracellular space but occurs within cells led to the surprising understanding that complement is involved in the regulation of basic processes of the cell, particularly those of metabolic nature—mostly via novel crosstalks between complement and intracellular sensor, and effector, pathways that had been overlooked because of their spatial separation. These paradigm shifts in the field led to a renaissance in complement research and provide new platforms to now better understand the molecular pathways underlying the wide-reaching effects of complement functions in immunity and beyond. In this review, we will cover the current knowledge about complement’s emerging relationship with the cellular metabolism machinery with a focus on the functional differences between serum-circulating versus intracellularly active complement during normal cell survival and induction of effector functions

  19. Heat differentiated complement factor profiling.

    Science.gov (United States)

    Hamsten, Carl; Skattum, Lillemor; Truedsson, Lennart; von Döbeln, Ulrika; Uhlén, Mathias; Schwenk, Jochen M; Hammarström, Lennart; Nilsson, Peter; Neiman, Maja

    2015-08-03

    Complement components and their cascade of reactions are important defense mechanisms within both innate and adaptive immunity. Many complement deficient patients still remain undiagnosed because of a lack of high throughput screening tools. Aiming towards neonatal proteome screening for immunodeficiencies, we used a multiplex profiling approach with antibody bead arrays to measure 9 complement proteins in serum and dried blood spots. Several complement components have been described as heat sensitive, thus their heat-dependent detectability was investigated. Using sera from 16 patients with complement deficiencies and 23 controls, we confirmed that the proteins C1q, C2, C3, C6, C9 and factor H were positively affected by heating, thus the identification of deficient patients was improved when preheating samples. Measurements of C7, C8 and factor I were negatively affected by heating and non-heated samples should be used in analysis of these components. In addition, a proof of concept study demonstrated the feasibility of labeling eluates from dried blood spots to perform a subsequent correct classification of C2-deficiencies. Our study demonstrates the potential of using multiplexed single binder assays for screening of complement components that open possibilities to expand such analysis to other forms of deficiencies.

  20. Complement factor B expression profile in a spontaneous uveitis model.

    Science.gov (United States)

    Zipplies, Johanna K; Kirschfink, Michael; Amann, Barbara; Hauck, Stefanie M; Stangassinger, Manfred; Deeg, Cornelia A

    2010-12-01

    Equine recurrent uveitis serves as a spontaneous model for human autoimmune uveitis. Unpredictable relapses and ongoing inflammation in the eyes of diseased horses as well as in humans lead to destruction of the retina and finally result in blindness. However, the molecular mechanisms leading to inflammation and retinal degeneration are not well understood. An initial screening for differentially regulated proteins in sera of uveitic cases compared to healthy controls revealed an increase of the alternative pathway complement component factor B in ERU cases. To determine the activation status of the complement system, sera were subsequently examined for complement split products. We could demonstrate a significant higher concentration of the activation products B/Ba, B/Bb, Bb neoantigen, iC3b and C3d in uveitic condition compared to healthy controls, whereas for C5b-9 no differences were detected. Additionally, we investigated complement activation directly in the retina by immunohistochemistry, since it is the main target organ of this autoimmune disease. Interestingly, infiltrating cells co-expressed activated factor Bb neoantigen, complement split product C3d as well as CD68, a macrophage marker. In this study, we could demonstrate activation of the complement system both systemically as well as in the eye, the target organ of spontaneous recurrent uveitis. Based on these novel findings, we postulate a novel role for macrophages in connection with complement synthesis at the site of inflammation.

  1. Complement involvement in periodontitis: molecular mechanisms and rational therapeutic approaches

    Science.gov (United States)

    Hajishengallis, George; Maekawa, Tomoki; Abe, Toshiharu; Hajishengallis, Evlambia; Lambris, John D.

    2015-01-01

    The complement system is a network of interacting fluid-phase and cell surface-associated molecules that trigger, amplify, and regulate immune and inflammatory signaling pathways. Dysregulation of this finely balanced network can destabilize host-microbe homeostasis and cause inflammatory tissue damage. Evidence from clinical and animal model-based studies suggests that complement is implicated in the pathogenesis of periodontitis, a polymicrobial community-induced chronic inflammatory disease that destroys the tooth-supporting tissues. This review discusses molecular mechanisms of complement involvement in the dysbiotic transformation of the periodontal microbiome and the resulting destructive inflammation, culminating in loss of periodontal bone support. These mechanistic studies have additionally identified potential therapeutic targets. In this regard, interventional studies in preclinical models have provided proof-of-concept for using complement inhibitors for the treatment of human periodontitis. PMID:26306443

  2. Complement sentences - complementizers of causative-manipulative verbs

    Directory of Open Access Journals (Sweden)

    Alanović Milivoj B.

    2015-01-01

    Full Text Available This paper presents the key structural and semantic features of the complement sentences that have the primary function of direct or indirect objects of one type of causative verbs - causative-manipulative verbs. Since the syntactic literature frequently discusses the structural characteristics of the complement sentences, the main objective of this article is focused on the semantic diversity of this type of sentences. The goal of the article is to determine the dependence of the realized meaning of a sentence on the semantic type of the main verb. Although the conjunction da is a typical subordinator of these sentences, a series of communicative verbs allows the use of complement sentences with interrogative adverbs and pronouns in the function of conjunctions. [Projekat Ministarstva nauke Republike Srbije, br.178004: Standardni srpski jezik - sintaksička, semantička i pragmatička istraživanja

  3. Functional analysis of Ficolin-3 mediated complement activation.

    Directory of Open Access Journals (Sweden)

    Estrid Hein

    Full Text Available The recognition molecules of the lectin complement pathway are mannose-binding lectin and Ficolin -1, -2 and -3. Recently deficiency of Ficolin-3 was found to be associated with life threatening infections. Thus, we aimed to develop a functional method based on the ELISA platform for evaluating Ficolin-3 mediated complement activation that could be applicable for research and clinical use. Bovine serum albumin (BSA was acetylated (acBSA and chosen as a solid phase ligand for Ficolins in microtiter wells. Binding of Ficolins on acBSA was evaluated, as was functional complement activation assessed by C4, C3 and terminal complement complex (TCC deposition. Serum Ficolin-3 bound to acBSA in a calcium dependent manner, while only minimal binding of Ficolin-2 and no binding of Ficolin-1 were observed. No binding to normal BSA was seen for any of the Ficolins. Serum C4, C3 and TCC deposition on acBSA were dependent only on Ficolin-3 in appropriate serum dilutions. Deposition of down stream complement components correlated highly significantly with the serum concentration of Ficolin-3 but not with Ficolin-2 in healthy donors. To make the assay robust for clinical use a chemical compound was applied to the samples that inhibited interference from the classical pathway due to the presence of anti-BSA antibodies in some sera. We describe a novel functional method for measuring complement activation mediated by Ficolin-3 in human serum up to the formation of TCC. The assay provides the possibility to diagnose functional and genetic defects of Ficolin-3 and down stream components in the lectin complement pathway.

  4. Genomes of parasitic nematodes (Meloidogyne hapla, Meloidogyne incognita, Ascaris suum and Brugia malayi) have a reduced complement of small RNA interference pathway genes: knockdown can reduce host infectivity of M. incognita.

    Science.gov (United States)

    Iqbal, Sadia; Fosu-Nyarko, John; Jones, Michael G K

    2016-07-01

    The discovery of RNA interference (RNAi) as an endogenous mechanism of gene regulation in a range of eukaryotes has resulted in its extensive use as a tool for functional genomic studies. It is important to study the mechanisms which underlie this phenomenon in different organisms, and in particular to understand details of the effectors that modulate its effectiveness. The aim of this study was to identify and compare genomic sequences encoding genes involved in the RNAi pathway of four parasitic nematodes: the plant parasites Meloidogyne hapla and Meloidogyne incognita and the animal parasites Ascaris suum and Brugia malayi because full genomic sequences were available-in relation to those of the model nematode Caenorhabditis elegans. The data generated was then used to identify some potential targets for control of the root knot nematode, M. incognita. Of the 84 RNAi pathway genes of C. elegans used as model in this study, there was a 42-53 % reduction in the number of effectors in the parasitic nematodes indicating substantial differences in the pathway between species. A gene each from six functional groups of the RNAi pathway of M. incognita was downregulated using in vitro RNAi, and depending on the gene (drh-3, tsn-1, rrf-1, xrn-2, mut-2 and alg-1), subsequent plant infection was reduced by up to 44 % and knockdown of some genes (i.e. drh-3, mut-2) also resulted in abnormal nematode development. The information generated here will contribute to defining targets for more robust nematode control using the RNAi technology.

  5. Functional analysis of Ficolin-3 mediated complement activation

    DEFF Research Database (Denmark)

    Hein, Estrid; Honoré, Christian; Skjoedt, Mikkel-Ole

    2010-01-01

    The recognition molecules of the lectin complement pathway are mannose-binding lectin and Ficolin -1, -2 and -3. Recently deficiency of Ficolin-3 was found to be associated with life threatening infections. Thus, we aimed to develop a functional method based on the ELISA platform for evaluating...... on acBSA were dependent only on Ficolin-3 in appropriate serum dilutions. Deposition of down stream complement components correlated highly significantly with the serum concentration of Ficolin-3 but not with Ficolin-2 in healthy donors. To make the assay robust for clinical use a chemical compound...... the possibility to diagnose functional and genetic defects of Ficolin-3 and down stream components in the lectin complement pathway....

  6. Complement monitoring of Pluronic 127 gel and micelles

    DEFF Research Database (Denmark)

    Hamad, Islam; Hunter, A Christy; Moghimi, Seyed Moien

    2013-01-01

    Poloxamer 407 is a non-ionic polyethylene oxide (PEO)/polypropylene oxide (PPO) block copolymer, which exhibits reversible thermogelation properties. Poloxamer gel has attracted many applications for controlled release of therapeutic agents as well as in surgical interventions such as controlled...... vascular occlusion. We show that poloxamer gel can trigger the complement system, which is an integral part of innate immunity and its inadvertent activation can induce clinically significant anaphylaxis. Complement activation by the poloxamer gel is through the alternative pathway, but material...... transformations from gel to the solution state further incite complement through calcium-sensitive pathways, where a role for C1q and antibodies has been eliminated. Poloxamer addition to plasma/serum (at levels above its critical micelle concentration, cmc) induced formation of large and diffused structures...

  7. Role of complement in IgA nephropathy.

    Science.gov (United States)

    Daha, Mohamed R; van Kooten, Cees

    2016-02-01

    Immunoglobulin A nephropathy (IgAN) is characterized by the deposition of IgA in the mesangium of glomeruli. This mesangial IgA has been found to consist mainly of polymeric IgA1 which drives the activation of the mesangial cells and results in excessive production of several inflammatory mediators. The activation of mesangial cells is amplified by the ability of IgA to activate the complement system, originally thought to occur mainly via the alternative pathway of complement. However more recent studies indicate that lectin pathway involvement has a strong association with progression of renal disease. In this review we summarize the contribution of complement to the IgA- mediated inflammatory process.

  8. Functional analysis of Ficolin-3 mediated complement activation

    DEFF Research Database (Denmark)

    Hein, Estrid; Honoré, Christian; Skjoedt, Mikkel-Ole;

    2010-01-01

    The recognition molecules of the lectin complement pathway are mannose-binding lectin and Ficolin -1, -2 and -3. Recently deficiency of Ficolin-3 was found to be associated with life threatening infections. Thus, we aimed to develop a functional method based on the ELISA platform for evaluating...

  9. Defining the complement biomarker profile of c3 glomerulopathy

    DEFF Research Database (Denmark)

    Zhang, Yuzhou; Nester, Carla M; Martin, Bertha;

    2014-01-01

    BACKGROUND AND OBJECTIVES: C3 glomerulopathy (C3G) applies to a group of renal diseases defined by a specific renal biopsy finding: a dominant pattern of C3 fragment deposition on immunofluorescence. The primary pathogenic mechanism involves abnormal control of the alternative complement pathway...

  10. Structural and functional characterization of human complement factor P

    DEFF Research Database (Denmark)

    Pedersen, Dennis

    2016-01-01

    The complement system is of great importance for the innate immune response, which can lead to opsonization and removal of invading pathogens, as well as immune complexes and damaged self-cells. Factor P (FP), also known as properdin, acts as a positive regulator of the alternative pathway...

  11. Complement inhibitory and anticoagulant activities of fractionated heparins

    NARCIS (Netherlands)

    Hennink, W.E.; Klerx, J.P.A.M.; Dijk, H. van; Feijen, J.

    1984-01-01

    Almost monodisperse heparin fractions (w/n < 1.1) were obtained by gel filtration of a commercial heparin. These fractions were assayed for anticoagulant activity (thrombin times and APTT), chromogenic anti-factor Xa activity, inhibitory activity for the human classical complement pathway, carboxyl

  12. CR2-mediated targeting of complement inhibitors: bench-to-bedside using a novel strategy for site-specific complement modulation.

    Science.gov (United States)

    Holers, V Michael; Rohrer, Bärbel; Tomlinson, Stephen

    2013-01-01

    Recent approval of the first human complement pathway-directed therapeutics, along with high-profile genetic association studies, has catalyzed renewed biopharmaceutical interest in developing drugs that modulate the complement system. Substantial challenges remain, however, that must be overcome before widespread application of complement inhibitors in inflammatory and autoimmune diseases becomes possible. Among these challenges are the following: (1) defining the complement pathways and effector mechanisms that cause tissue injury in humans and determining whether the relative importance of each varies by disease, (2) blocking or modulating, using traditional small molecule or biologic approaches, the function of complement proteins whose circulating levels are very high and whose turnover rates are relatively rapid, especially in the setting of acute and chronic autoimmune diseases, and (3) avoiding infectious complications or impairment of other important physiological functions of complement when using systemically active complement-blocking agents. This chapter will review data that address these challenges to therapeutic development, with a focus on the development of a novel strategy of blocking specific complement pathways by targeting inhibitors using a recombinant portion of the human complement receptor type 2 (CR2/CD21) which specifically targets to sites of local complement C3 activation where C3 fragments are covalently fixed. Recently, the first of these CR2-targeted proteins has entered human phase I studies in the human disease paroxysmal nocturnal hemoglobinuria. The results of murine translational studies using CR2-targeted inhibitors strongly suggest that a guiding principle going forward in complement therapeutic development may well be to focus on developing strategies to modulate the pathway as precisely as possible by physically localizing therapeutic inhibitory effects.

  13. Parental genome dosage imbalance deregulates imprinting in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Pauline E Jullien

    2010-03-01

    Full Text Available In mammals and in plants, parental genome dosage imbalance deregulates embryo growth and might be involved in reproductive isolation between emerging new species. Increased dosage of maternal genomes represses growth while an increased dosage of paternal genomes has the opposite effect. These observations led to the discovery of imprinted genes, which are expressed by a single parental allele. It was further proposed in the frame of the parental conflict theory that parental genome imbalances are directly mirrored by antagonistic regulations of imprinted genes encoding maternal growth inhibitors and paternal growth enhancers. However these hypotheses were never tested directly. Here, we investigated the effect of parental genome imbalance on the expression of Arabidopsis imprinted genes FERTILIZATION INDEPENDENT SEED2 (FIS2 and FLOWERING WAGENINGEN (FWA controlled by DNA methylation, and MEDEA (MEA and PHERES1 (PHE1 controlled by histone methylation. Genome dosage imbalance deregulated the expression of FIS2 and PHE1 in an antagonistic manner. In addition increased dosage of inactive alleles caused a loss of imprinting of FIS2 and MEA. Although FIS2 controls histone methylation, which represses MEA and PHE1 expression, the changes of PHE1 and MEA expression could not be fully accounted for by the corresponding fluctuations of FIS2 expression. Our results show that parental genome dosage imbalance deregulates imprinting using mechanisms, which are independent from known regulators of imprinting. The complexity of the network of regulations between expressed and silenced alleles of imprinted genes activated in response to parental dosage imbalance does not support simple models derived from the parental conflict hypothesis.

  14. Parental genome dosage imbalance deregulates imprinting in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Pauline E Jullien

    2010-03-01

    Full Text Available In mammals and in plants, parental genome dosage imbalance deregulates embryo growth and might be involved in reproductive isolation between emerging new species. Increased dosage of maternal genomes represses growth while an increased dosage of paternal genomes has the opposite effect. These observations led to the discovery of imprinted genes, which are expressed by a single parental allele. It was further proposed in the frame of the parental conflict theory that parental genome imbalances are directly mirrored by antagonistic regulations of imprinted genes encoding maternal growth inhibitors and paternal growth enhancers. However these hypotheses were never tested directly. Here, we investigated the effect of parental genome imbalance on the expression of Arabidopsis imprinted genes FERTILIZATION INDEPENDENT SEED2 (FIS2 and FLOWERING WAGENINGEN (FWA controlled by DNA methylation, and MEDEA (MEA and PHERES1 (PHE1 controlled by histone methylation. Genome dosage imbalance deregulated the expression of FIS2 and PHE1 in an antagonistic manner. In addition increased dosage of inactive alleles caused a loss of imprinting of FIS2 and MEA. Although FIS2 controls histone methylation, which represses MEA and PHE1 expression, the changes of PHE1 and MEA expression could not be fully accounted for by the corresponding fluctuations of FIS2 expression. Our results show that parental genome dosage imbalance deregulates imprinting using mechanisms, which are independent from known regulators of imprinting. The complexity of the network of regulations between expressed and silenced alleles of imprinted genes activated in response to parental dosage imbalance does not support simple models derived from the parental conflict hypothesis.

  15. A congestion line flow control in deregulated power system

    Directory of Open Access Journals (Sweden)

    Venkatarajan Shanmuga Sundaram

    2011-01-01

    Full Text Available Under open access, market-driven transactions have become the new independent decision variables defining the behavior of the power system. The possibility of transmission lines getting over-loaded is relatively more under deregulated operation because different parts of the system are owned by separate companies and in part operated under varying service charges. This paper discusses a two-tier algorithm for correcting the lone overloads in conjunction with the conventional power-flow methods. The method uses line flow sensitivities, which are computed by the East Decoupled Power-flow algorithm and can be adapted for on-line implementation.

  16. Power systems locational marginal pricing in deregulated markets

    Science.gov (United States)

    Wang, Hui-Fung Francis

    Since the beginning of the 1990s, the electricity business is transforming from a vertical integrating business to a competitive market operations. The generation, transmission, distribution subsystem of an electricity utility are operated independently as Genco (generation subsystem), Transco (transmission subsystem), and Distco (distribution subsystem). This trend promotes more economical inter- and intra regional transactions to be made by the participating companies and the users of electricity to achieve the intended objectives of deregulation. There are various types of electricity markets that are implemented in the North America in the past few years. However, transmission congestion management becomes a key issue in the electricity market design as more bilateral transactions are traded across long distances competing for scarce transmission resources. It directly alters the traditional concept of energy pricing and impacts the bottom line, revenue and cost of electricity, of both suppliers and buyers. In this research, transmission congestion problem in a deregulated market environment is elucidated by implementing by the Locational Marginal Pricing (LMP) method. With a comprehensive understanding of the LMP method, new mathematical tools will aid electric utilities in exploring new business opportunities are developed and presented in this dissertation. The dissertation focuses on the development of concept of (LMP) forecasting and its implication to the market participants in deregulated market. Specifically, we explore methods of developing fast LMP calculation techniques that are differ from existing LMPs. We also explore and document the usefulness of the proposed LMP in determining electricity pricing of a large scale power system. The developed mathematical tools use of well-known optimization techniques such as linear programming that are support by several flow charts. The fast and practical security constrained unit commitment methods are the

  17. Energy and the aged: the impact of natural gas deregulation

    Energy Technology Data Exchange (ETDEWEB)

    1983-01-01

    Energy Secretary Donald Hodel led a group of six witnesses at a hearing held to examine the potential impact of natural gas deregulation proposals on elderly consumers. The witnesses were asked to examine the impact of current price increases on residential users, review anticipated price changes for elderly consumers, and explore whether current resources to offset these impacts on low-income and elderly consumers are adequate. Hodel's testimony is followed by that of representatives of public utility commissions and consumer groups and by an appendix with analyses by the DOE and the National Consumer Law Center.

  18. Role of deregulated microRNAs in breast cancer progression using FFPE tissue.

    Directory of Open Access Journals (Sweden)

    Liang Chen

    Full Text Available MicroRNAs (miRNAs contribute to cancer initiation and progression by silencing the expression of their target genes, causing either mRNA molecule degradation or translational inhibition. Intraductal epithelial proliferations of the breast are histologically and clinically classified into normal, atypical ductal hyperplasia (ADH, ductal carcinoma in situ (DCIS and invasive ductal carcinoma (IDC. To better understand the progression of ductal breast cancer development, we attempt to identify deregulated miRNAs in this process using Formalin-Fixed, Paraffin-Embedded (FFPE tissues from breast cancer patients. Following tissue microdissection, we obtained 8 normal, 4 ADH, 6 DCIS and 7 IDC samples, which were subject to RNA isolation and miRNA expression profiling analysis. We found that miR-21, miR-200b/c, miR-141, and miR-183 were consistently up-regulated in ADH, DCIS and IDC compared to normal, while miR-557 was uniquely down-regulated in DCIS. Interestingly, the most significant miRNA deregulations occurred during the transition from normal to ADH. However, the data did not reveal a step-wise miRNA alteration among discrete steps along tumor progression, which is in accordance with previous reports of mRNA profiling of different stages of breast cancer. Furthermore, the expression of MSH2 and SMAD7, two important molecules involving TGF-β pathway, was restored following miR-21 knockdown in both MCF-7 and Hs578T breast cancer cells. In this study, we have not only identified a number of potential candidate miRNAs for breast cancer, but also found that deregulation of miRNA expression during breast tumorigenesis might be an early event since it occurred significantly during normal to ADH transition. Consequently, we have demonstrated the feasibility of miRNA expression profiling analysis using archived FFPE tissues, typically with rich clinical information, as a means of miRNA biomarker discovery.

  19. Inefficient complement system clearance of Trypanosoma cruzi metacyclic trypomastigotes enables resistant strains to invade eukaryotic cells.

    Directory of Open Access Journals (Sweden)

    Igor Cestari

    Full Text Available The complement system is the main arm of the vertebrate innate immune system against pathogen infection. For the protozoan Trypanosoma cruzi, the causative agent of Chagas disease, subverting the complement system and invading the host cells is crucial to succeed in infection. However, little attention has focused on whether the complement system can effectively control T. cruzi infection. To address this question, we decided to analyse: 1 which complement pathways are activated by T. cruzi using strains isolated from different hosts, 2 the capacity of these strains to resist the complement-mediated killing at nearly physiological conditions, and 3 whether the complement system could limit or control T. cruzi invasion of eukaryotic cells. The complement activating molecules C1q, C3, mannan-binding lectin and ficolins bound to all strains analysed; however, C3b and C4b deposition assays revealed that T. cruzi activates mainly the lectin and alternative complement pathways in non-immune human serum. Strikingly, we detected that metacyclic trypomastigotes of some T. cruzi strains were highly susceptible to complement-mediated killing in non-immune serum, while other strains were resistant. Furthermore, the rate of parasite invasion in eukaryotic cells was decreased by non-immune serum. Altogether, these results establish that the complement system recognizes T. cruzi metacyclic trypomastigotes, resulting in killing of susceptible strains. The complement system, therefore, acts as a physiological barrier which resistant strains have to evade for successful host infection.

  20. Force Dynamics of Verb Complementation

    Directory of Open Access Journals (Sweden)

    Jacek Woźny

    2015-12-01

    Full Text Available Force Dynamics of Verb Complementation The concepts of motion and force are both extensively discussed in cognitive linguistics literature. But they are discussed separately. The first usually in the context of ‘motion situations’ (Talmy, Slobin, Zlatev, the other as part of the Force Dynamics framework, which was developed by Talmy. The aim of this paper is twofold: first, to argue that the concepts of force and motion should not be isolated but considered as two inseparable parts of force-motion events. The second goal is to prove that the modified Force Dynamics (force-motion framework can be used for precise characterization of the verb complementation patterns. To this end, a random sample of 50 sentences containing the verb ‘went’ is analyzed, demonstrating the differences between the categories of intensive and intransitive complementation with respect to the linguistically coded parameters of force and motion.

  1. Complement's participation in acquired immunity

    DEFF Research Database (Denmark)

    Nielsen, Claus Henrik; Leslie, Robert Graham Quinton

    2002-01-01

    of the B cell receptor for antigen (BCR), a complex composed of the iC3b/C3d fragment-binding complement type 2 receptor (CR2, CD21) and its signaling element CD19 and the IgG-binding receptor FcgammaRIIb (CD32). The positive or negative outcome of signaling through this triad is determined by the context...... in which antigen is seen, be it alone or in association with natural or induced antibodies and/or C3-complement fragments. The aim of this review is to describe the present status of our understanding of complement's participation in acquired immunity and the regulation of autoimmune responses....

  2. Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation

    Science.gov (United States)

    Hasumi, Yukiko; Baba, Masaya; Hasumi, Hisashi; Huang, Ying; Lang, Martin; Reindorf, Rachel; Oh, Hyoung-bin; Sciarretta, Sebastiano; Nagashima, Kunio; Haines, Diana C.; Schneider, Michael D.; Adelstein, Robert S.; Schmidt, Laura S.; Sadoshima, Junichi; Marston Linehan, W.

    2014-01-01

    Cardiac hypertrophy, an adaptive process that responds to increased wall stress, is characterized by the enlargement of cardiomyocytes and structural remodeling. It is stimulated by various growth signals, of which the mTORC1 pathway is a well-recognized source. Here, we show that loss of Flcn, a novel AMPK–mTOR interacting molecule, causes severe cardiac hypertrophy with deregulated energy homeostasis leading to dilated cardiomyopathy in mice. We found that mTORC1 activity was upregulated in Flcn-deficient hearts, and that rapamycin treatment significantly reduced heart mass and ameliorated cardiac dysfunction. Phospho-AMP-activated protein kinase (AMPK)-alpha (T172) was reduced in Flcn-deficient hearts and nonresponsive to various stimulations including metformin and AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide). ATP levels were elevated and mitochondrial function was increased in Flcn-deficient hearts, suggesting that excess energy resulting from up-regulated mitochondrial metabolism under Flcn deficiency might attenuate AMPK activation. Expression of Ppargc1a, a central molecule for mitochondrial metabolism, was increased in Flcn-deficient hearts and indeed, inactivation of Ppargc1a in Flcn-deficient hearts significantly reduced heart mass and prolonged survival. Ppargc1a inactivation restored phospho-AMPK-alpha levels and suppressed mTORC1 activity in Flcn-deficient hearts, suggesting that up-regulated Ppargc1a confers increased mitochondrial metabolism and excess energy, leading to inactivation of AMPK and activation of mTORC1. Rapamycin treatment did not affect the heart size of Flcn/Ppargc1a doubly inactivated hearts, further supporting the idea that Ppargc1a is the critical element leading to deregulation of the AMPK–mTOR-axis and resulting in cardiac hypertrophy under Flcn deficiency. These data support an important role for Flcn in cardiac homeostasis in the murine model. PMID:24908670

  3. Micrurus snake venoms activate human complement system and generate anaphylatoxins

    Directory of Open Access Journals (Sweden)

    Tanaka Gabriela D

    2012-01-01

    Full Text Available Abstract Background The genus Micrurus, coral snakes (Serpentes, Elapidae, comprises more than 120 species and subspecies distributed from the south United States to the south of South America. Micrurus snake bites can cause death by muscle paralysis and further respiratory arrest within a few hours after envenomation. Clinical observations show mainly neurotoxic symptoms, although other biological activities have also been experimentally observed, including cardiotoxicity, hemolysis, edema and myotoxicity. Results In the present study we have investigated the action of venoms from seven species of snakes from the genus Micrurus on the complement system in in vitro studies. Several of the Micrurus species could consume the classical and/or the lectin pathways, but not the alternative pathway, and C3a, C4a and C5a were generated in sera treated with the venoms as result of this complement activation. Micrurus venoms were also able to directly cleave the α chain of the component C3, but not of the C4, which was inhibited by 1,10 Phenanthroline, suggesting the presence of a C3α chain specific metalloprotease in Micrurus spp venoms. Furthermore, complement activation was in part associated with the cleavage of C1-Inhibitor by protease(s present in the venoms, which disrupts complement activation control. Conclusion Micrurus venoms can activate the complement system, generating a significant amount of anaphylatoxins, which may assist due to their vasodilatory effects, to enhance the spreading of other venom components during the envenomation process.

  4. Artificial intelligence methods in deregulated power systems operations

    Science.gov (United States)

    Ilic, Jovan

    With the introduction of the power systems deregulation, many classical power transmission and distribution optimization tools became inadequate. Optimal Power Flow and Unit Commitment are common computer programs used in the regulated power industry. This work is addressing the Optimal Power Flow and Unit Commitment in the new deregulated environment. Optimal Power Flow is a high dimensional, non-linear, and non-convex optimization problem. As such, it is even now, after forty years since its introduction, a research topic without a widely accepted solution able to encompass all areas of interest. Unit Commitment is a high dimensional, combinatorial problem which should ideally include the Optimal Power Flow in its solution. The dimensionality of a typical Unit Commitment problem is so great that even the enumeration of all the combinations would take too much time for any practical purposes. This dissertation attacks the Optimal Power Flow problem using non-traditional tools from the Artificial Intelligence arena. Artificial Intelligence optimization methods are based on stochastic principles. Usually, stochastic optimization methods are successful where all other classical approaches fail. We will use Genetic Programming optimization for both Optimal Power Flow and Unit Commitment. Long processing times will also be addressed through supervised machine learning.

  5. Hydro reservoir handling in Norway before and after deregulation

    Energy Technology Data Exchange (ETDEWEB)

    Wolfgang, Ove; Haugstad, Arne; Mo, Birger; Gjelsvik, Anders [SINTEF Energy Research, 7465 Trondheim (Norway); Wangensteen, Ivar; Doorman, Gerard [NTNU, Department of Electric Power Engineering, 7491 Trondheim (Norway)

    2009-10-15

    The Norwegian Energy Act that came into force in 1991 deregulated the electricity market and removed the former obligation power companies had to supply electricity to the geographical area they were responsible for. Hence producers can supply electricity on the basis of profitability. In 2007 the Energy Act was evaluated by the Government. As a part of this, a study concerning hydro reservoir handling before and after deregulation was carried out by SINTEF. Public statistics show that average hydro reservoir levels measured in per cent of reservoir capacity have been reduced after 1990. We have used the power-market model EMPS (EFI's Multi-area Power-market Simulator) to analyze if this reduction can be explained by natural variation in climatic variables or by structural changes that have occurred after 1990. Simulation results show that the reduced reservoir levels cannot be explained by natural variation in climatic variables. Structural changes such as increased transmission capacities can, however, explain some of the reduction. Our study does not indicate that the present reservoir handling gives reservoir levels that are too low. In this paper we also describe the stochastic dynamic optimization problem for long-term hydropower scheduling, and we explain how this problem actually is solved by the EMPS model. (author)

  6. Bluewater Power goes ERP route to address deregulation : case study

    Energy Technology Data Exchange (ETDEWEB)

    Broad, K. [Bluewater Power Distribution Corp., Sarnia, ON (Canada)

    2009-05-15

    Bluewater Power Distribution Corporation distributes electricity to 35,000 customers in southwestern Ontario, including residential customers, large industries and commercial establishments. Their distribution system network consists of more than 344 miles of overhead wires and 125 miles of underground wires. The company employs more than 90 full-time people and is the result of a merger of six local utilities in year 2000. Ontario's energy market was preparing to deregulate at the time of the merger. Under the deregulation rules, utilities in the province were required to provide unbundled bills and exchange customer electronic business transactions with energy retailers. New rules opened up the cost of power on the wholesale side, requiring utilities to conduct wholesale settlements with the Independent Electricity System Operator (IESO). The IESO manages Ontario's bulk electricity power system and operates the wholesale market. This article described the solution that Bluewater Power's information technology (IT) team found to support Ontario's local market, meet regulatory demands and adapt to future regulatory changes.

  7. Complement: Alive and Kicking Nanomedicines

    DEFF Research Database (Denmark)

    Andersen, Alina Joukainen; Hashemi, S.H.; Andresen, Thomas Lars;

    2009-01-01

    Administration of liposome- and polymer-based clinical nanomedicines, as well as many other proposed multifunctional nanoparticles, often triggers hypersensitivity reactions without the involvement of IgE. These anaphylactic reactions are believed to be secondary to activation of the complement s...

  8. Milk immunoglobulins and complement factors.

    Science.gov (United States)

    Korhonen, H; Marnila, P; Gill, H S

    2000-11-01

    The importance of colostrum for the growth and health of newborn offspring is well known. In bovine colostrum, the antibody (immunoglobulin) complement system provides a major antimicrobial effect against a wide range of microbes and confers passive immunity until the calf's own immune system has matured. Bovine serum and lacteal secretions contain three major classes of immunoglobulins: IgG, IgM and IgA. The immunoglobulins are selectively transported from the serum into the mammary gland, as a result of which the first colostrum contains very high concentrations of immunoglobulins (40-200 mg/ml). IgG1 accounts for over 75 % of the immunoglobulins in colostral whey, followed by IgM, IgA and IgG2. All these immunoglobulins decrease within a few days to a total immunoglobulin concentration of 0.7-1.0 mg/ml, with IgG1 representing the major Ig class in milk throughout the lactation period. Together with the antibodies absorbed from colostrum after birth, the complement system plays a crucial role in the passive immunisation of the newborn calf. The occurrence of haemolytic or bactericidal complement activity in bovine colostrum and milk has been demonstrated in several studies. This review deals with the characteristics of bovine Igs and the complement system to be exploited as potential ingredients for health-promoting functional foods.

  9. Role of complement in xenotransplantation.

    Science.gov (United States)

    Mollnes, Tom Eirik; Fiane, A E

    2002-01-01

    The xenotransplantation research is driven by the increasing gap between the number of patients with end-stage organ failure on waiting lists for transplantation and the supply of allografts. The lack of success in developing suitable artificial organs for permanent treatment of organ failure has further strengthened the need for xenotransplantation research. Pigs are now generally accepted to be the source animal of choice. Transplantation of pig organs to humans faces several barriers which have to be overcome before it comes to clinical application: (1) anatomical and physiological conditions; (2) immunological rejection mechanisms; (3) molecular compatibility between signal molecules of the two species; (4) risk of transmission of microorganisms, particularly pig endogenous retroviruses; and (5) legal and ethical aspects both with respect to the animal and the recipient. Here we will focus on the role of the complement system in the rejection of immediately vascularized pig-to-primate xenografts. The hyperacute rejection occurring within minutes after transplantation is mediated by binding of natural antibodies to the Galalpha(l-3)Gal epitope on the endothelial cells with subsequent complement activation. Whereas inhibition of complement activation protects against hyperacute rejection, the role of complement in the later rejection phases is less clarified.

  10. Bullous pemphigoid autoantibodies directly induce blister formation without complement activation.

    Science.gov (United States)

    Ujiie, Hideyuki; Sasaoka, Tetsumasa; Izumi, Kentaro; Nishie, Wataru; Shinkuma, Satoru; Natsuga, Ken; Nakamura, Hideki; Shibaki, Akihiko; Shimizu, Hiroshi

    2014-11-01

    Complement activation and subsequent recruitment of inflammatory cells at the dermal/epidermal junction are thought to be essential for blister formation in bullous pemphigoid (BP), an autoimmune blistering disease induced by autoantibodies against type XVII collagen (COL17); however, this theory does not fully explain the pathological features of BP. Recently, the involvement of complement-independent pathways has been proposed. To directly address the question of the necessity of the complement activation in blister formation, we generated C3-deficient COL17-humanized mice. First, we show that passive transfer of autoantibodies from BP patients induced blister formation in neonatal C3-deficient COL17-humanized mice without complement activation. By using newly generated human and murine mAbs against the pathogenic noncollagenous 16A domain of COL17 with high (human IgG1, murine IgG2), low (murine IgG1), or no (human IgG4) complement activation abilities, we demonstrate that the deposition of Abs, and not complements, is relevant to the induction of blister formation in neonatal and adult mice. Notably, passive transfer of BP autoantibodies reduced the amount of COL17 in lesional mice skin, as observed in cultured normal human keratinocytes treated with the same Abs. Moreover, the COL17 depletion was associated with a ubiquitin/proteasome pathway. In conclusion, the COL17 depletion induced by BP autoantibodies, and not complement activation, is essential for the blister formation under our experimental system. Copyright © 2014 by The American Association of Immunologists, Inc.

  11. 21 CFR 866.4100 - Complement reagent.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Complement reagent. 866.4100 Section 866.4100 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL... Complement reagent. (a) Identification. A complement reagent is a device that consists of complement,...

  12. Complement activation in the context of stem cells and tissue repair

    Institute of Scientific and Technical Information of China (English)

    Ingrid; U; Schraufstatter; Sophia; K; Khaldoyanidi; Richard; G; DiScipio

    2015-01-01

    The complement pathway is best known for its role in immune surveillance and inflammation. However,its ability of opsonizing and removing not only pathogens,but also necrotic and apoptotic cells,is a phylogenetically ancient means of initiating tissue repair. The means and mechanisms of complement-mediated tissue repair are discussed in this review. There is increasing evidence that complement activation contributes to tissue repair at several levels. These range from the chemo-attraction of stem and progenitor cells to areas of complement activation,to increased survival of various cell types in the presence of split products of complement,and to the production of trophic factors by cells activated by the anaphylatoxins C3 a and C5 a. This repair aspect of complement biology has not found sufficient appreciation until recently. The following will examine this aspect of complement biology with an emphasis on the anaphylatoxins C3 a and C5 a.

  13. Metabolic Complementation in Bacterial Communities: Necessary Conditions and Optimality

    Science.gov (United States)

    Mori, Matteo; Ponce-de-León, Miguel; Peretó, Juli; Montero, Francisco

    2016-01-01

    Bacterial communities may display metabolic complementation, in which different members of the association partially contribute to the same biosynthetic pathway. In this way, the end product of the pathway is synthesized by the community as a whole. However, the emergence and the benefits of such complementation are poorly understood. Herein, we present a simple model to analyze the metabolic interactions among bacteria, including the host in the case of endosymbiotic bacteria. The model considers two cell populations, with both cell types encoding for the same linear biosynthetic pathway. We have found that, for metabolic complementation to emerge as an optimal strategy, both product inhibition and large permeabilities are needed. In the light of these results, we then consider the patterns found in the case of tryptophan biosynthesis in the endosymbiont consortium hosted by the aphid Cinara cedri. Using in-silico computed physicochemical properties of metabolites of this and other biosynthetic pathways, we verified that the splitting point of the pathway corresponds to the most permeable intermediate. PMID:27774085

  14. Reincarnation of ancient links between coagulation and complement.

    Science.gov (United States)

    Conway, E M

    2015-06-01

    Throughout evolution, organisms have developed means to contain wounds by simultaneously limiting bleeding and eliminating pathogens and damaged host cells via the recruitment of innate defense mechanisms. Disease emerges when there is unchecked activation of innate immune and/or coagulation responses. A key component of innate immunity is the complement system. Concurrent excess activation of coagulation and complement - two major blood-borne proteolytic pathways - is evident in numerous diseases, including atherosclerosis, diabetes, venous thromboembolic disease, thrombotic microangiopathies, arthritis, cancer, and infectious diseases. Delineating the cross-talk between these two cascades will uncover novel therapeutic insights.

  15. Functional analysis of Ficolin-3 mediated complement activation

    DEFF Research Database (Denmark)

    Hein, Estrid; Honoré, Christian; Skjoedt, Mikkel-Ole

    2010-01-01

    assessed by C4, C3 and terminal complement complex (TCC) deposition. Serum Ficolin-3 bound to acBSA in a calcium dependent manner, while only minimal binding of Ficolin-2 and no binding of Ficolin-1 were observed. No binding to normal BSA was seen for any of the Ficolins. Serum C4, C3 and TCC deposition...... was applied to the samples that inhibited interference from the classical pathway due to the presence of anti-BSA antibodies in some sera. We describe a novel functional method for measuring complement activation mediated by Ficolin-3 in human serum up to the formation of TCC. The assay provides...

  16. Exploring the Innate Immune System: Using Complement-Medicated Cell Lysis in the Classroom

    Science.gov (United States)

    Fuller, Kevin G.

    2008-01-01

    The protein complement pathway comprises an important part of the innate immunity. The use of serum to demonstrate complement-mediated destruction across a series of bacterial dilutions allows an instructor to introduce a number of important biological concepts such as bacterial growth, activation cascades, and adaptive versus innate immunity.

  17. Role of complement in in vitro and in vivo lung inflammatory reactions

    DEFF Research Database (Denmark)

    Czermak, B J; Lentsch, A B; Bless, N M

    1998-01-01

    requirement for full expression of lung injury is demonstrated, as are the involved intracellular signal transduction pathways. Understanding the mechanisms of complement-induced proinflammatory effects may provide a basis for future therapeutic blockade of complement and/or its activation products....

  18. Complement activation patterns in atypical haemolytic uraemic syndrome during acute phase and in remission

    NARCIS (Netherlands)

    Volokhina, E.B.; Westra, D.; Velden, T.J.A.M. van der; Kar, N.C.A.J. van de; Mollnes, T.E.; Heuvel, B. van den

    2015-01-01

    Atypical haemolytic uraemic syndrome (aHUS) is associated with (genetic) alterations in alternative complement pathway. Nevertheless, comprehensive evidence that the complement system in aHUS patients is more prone to activation is still lacking. Therefore, we performed a thorough analysis of comple

  19. Inhibition of classical complement activation attenuates liver ischaemia and reperfusion injury in a rat model

    NARCIS (Netherlands)

    B.H.M. Heijnen; I.H. Straatsburg; N.D. Padilla; G.J. Mierlo; C.E. Hack; T.M. van Gulik

    2006-01-01

    Activation of the complement system contributes to the pathogenesis of ischaemia/reperfusion (I/R) injury. We evaluated inhibition of the classical pathway of complement using C1-inhibitor (C1-inh) in a model of 70% partial liver I/R injury in male Wistar rats (n = 35). C1-inh was administered at 10

  20. Air pollution effects due to deregulation of the electric industry

    Science.gov (United States)

    Davoodi, Khojasteh Riaz

    The Energy Policy Act of 1992 introduced the concept of open-access into the electric utility industry which allows privately-owned utilities to transmit power produced by non-utility generators and independent power producers (IPPs). In April 1996, the Federal Energy Regulatory Commission (FERC) laid down the final rules (Orders No. 888 & No. 889), which required utilities to open their transmission lines to any power producer and charge them no more than what they pay for the use of their own lines. These rules set the stage for the retail sale of electricity to industrial, commercial and residential utility customers; non-utility generators (Nugs); and power marketers. These statutory, regulatory and administrative changes create for the electric utility industry two different forces that contradict each other. The first is the concept of competition among utility companies; this places a greater emphasis on electric power generation cost control and affects generation/fuel mix selection and demand side management (DSM) activities. The second force, which is converse to the first, is that utilities are major contributors to the air pollution burden in the United States and environmental concerns are forcing them to reduce emissions of air pollutants by using more environmentally friendly fuels and implementing energy saving programs. This study evaluates the impact of deregulation within the investor owned electric utilities and how this deregulation effects air quality by investigating the trend in demand side management programs and generation/fuel mix. A survey was conducted of investor owned utilities and independent power producers. The results of the survey were analyzed by analysis of variance and regression analysis to determine the impact to Air Pollution. An air Quality Impact model was also developed in this study. This model consists of six modules: (1) demand side management and (2) consumption of coal, (3) gas, (4) renewable, (5) oil and (6

  1. IgG4 anti-phospholipase A2 receptor might activate lectin and alternative complement pathway meanwhile in idiopathic membranous nephropathy: an inspiration from a cross-sectional study.

    Science.gov (United States)

    Yang, Yang; Wang, Chao; Jin, Liping; He, Fagui; Li, Changchun; Gao, Qingman; Chen, Guanglei; He, Zhijun; Song, Minghui; Zhou, Zhuliang; Shan, Fujun; Qi, Ka; Ma, Lu

    2016-08-01

    The deposition of IgG4 of antibodies against phospholipase A2 receptor (anti-PLA2R) is predominating in the kidneys of patients with idiopathic membranous nephropathy, while its predictive value has not been determined. It was a retrospective study, and 438 patients were included. Serum samples of two time points [before intervention (baseline) and after 1.5-year treatment (endpoint)] were detected for total and IgG4 anti-PLA2R. IgG4 PLA2R was a useful predictor for achieving CR, but there was a high heterogeneity; (2) there was significant correlation between the baseline and decrease in IgG4 subclass and the achievement of CR; (3) bi-negativity of IgG4 has a high accuracy of predicting CR compared with total antibodies; (4) in patients of bi-positivity, those achieving CR showed lower MASP-1/2, MBL, C3a, C5a, FB, Ba and Bb than patients failing to achieve CR; (5) the titers of endpoint and decrease in Ba and Bb were associated with improvement of 24 h-UP in those of bi-positivity; and (6) the decrease in Ba was a significant factor for achieving CR in those of bi-positivity. Continuous IgG4 negativity was a useful tool to predict the achievement of CR; however, in patients of continuous IgG4 positivity, those with lower activation of lectin and alternative pathways would still more probably achieve CR.

  2. Complement evasion by Plasmodium falciparum

    OpenAIRE

    Holopainen, Saila

    2008-01-01

    Patologian oppiaine Malaria remains one of the major health problems in many tropical countries, especially in sub-Saharan Africa. Among the most characteristic features of the malaria pathogens, protozoan parasites of the genus Plasmodium, is their ability to evade the immune defences of the host for extended periods of time. The complement system (C) is an essential part of the innate system in the first line of defense. It consists of over 30 soluble or membrane-bound components. C...

  3. Complement Activation Alters Platelet Function

    Science.gov (United States)

    2015-12-01

    Award Number: W81XWH-12-1-0523 TITLE: Complement Activation Alters Platelet Function PRINCIPAL INVESTIGATOR: George Tsokos, M.D. CONTRACTING...Activation Alters Platelet Function 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-12-1-0523 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) George Tsokos, M.D...a decreased level of disease. Further studies will expand upon these observations better outlining the function of platelets in the injury associated

  4. Steady state security assessment in deregulated power systems

    Science.gov (United States)

    Manjure, Durgesh Padmakar

    Power system operations are undergoing changes, brought about primarily due to deregulation and subsequent restructuring of the power industry. The primary intention of the introduction of deregulation in power systems was to bring about competition and improved customer focus. The underlying motive was increased economic benefit. Present day power system analysis is much different than what it was earlier, essentially due to the transformation of the power industry from being cost-based to one that is price-based and due to open access of transmission networks to the various market participants. Power is now treated as a commodity and is traded in an open market. The resultant interdependence of the technical criteria and the economic considerations has only accentuated the need for accurate analysis in power systems. The main impetus in security analysis studies is on efficient assessment of the post-contingency status of the system, accuracy being of secondary consideration. In most cases, given the time frame involved, it is not feasible to run a complete AC load flow for determining the post-contingency state of the system. Quite often, it is not warranted as well, as an indication of the state of the system is desired rather than the exact quantification of the various state variables. With the inception of deregulation, transmission networks are subjected to a host of multilateral transactions, which would influence physical system quantities like real power flows, security margins and voltage levels. For efficient asset utilization and maximization of the revenue, more often than not, transmission networks are operated under stressed conditions, close to security limits. Therefore, a quantitative assessment of the extent to which each transaction adversely affects the transmission network is required. This needs to be done accurately as the feasibility of the power transactions and subsequent decisions (execution, curtailment, pricing) would depend upon the

  5. Recovery of stranded costs under electric deregulation: The Winstar doctrine

    Energy Technology Data Exchange (ETDEWEB)

    Person, J.C. [Person and Craver, Washington, DC (United States)

    1998-12-31

    This paper explores the applicability of the Winstar doctrine to the recovery of stranded costs arising from the deregulation of the electric utility industry. Such stranded costs, which have been widely estimated to be in the $100--200 billion range, represent those utility assets whose book value exceed their market value. Not addressed in this paper are the ongoing state and federal legislative initiatives to allow for the recovery of some or all of a utility`s stranded costs, such as through the assessment of competitive transmission charges (CTCs) or through stranded cost securitization. Rather, this paper presents one of several of legal arguments that could be utilized in those situations where a legislative solution either does not exist or does not allow for full book value recovery.

  6. Pricing and University Autonomy: Tuition Deregulation in Texas

    Directory of Open Access Journals (Sweden)

    Jeongeun Kim

    2016-04-01

    Full Text Available This paper investigates changes in tuition policies in the wake of tuition deregulation in Texas, which in 2003 transferred tuition-setting authority from the state legislature to institutions. We find that price increases accelerated, particularly at the most selective institutions. Institutions also began differentiating price by undergraduate program, raising relative prices for the most costly and lucrative majors, including engineering, business, nursing, and architecture. Price increases were particularly large for institutions with the highest initial costs and for programs with a high earnings premium within institutions, though lower for institutions with more low-income students. These distinctions suggest that public postsecondary institutions respond to microeconomic incentives when given greater autonomy to set price, and take some measures to alleviate impacts on low-income students. The Texas experience suggests that decentralized price-setting generates greater price differentiation within the public higher education system, both across and within institutions.

  7. Voltage stability analysis in the new deregulated environment

    Science.gov (United States)

    Zhu, Tong

    Nowadays, a significant portion of the power industry is under deregulation. Under this new circumstance, network security analysis is more critical and more difficult. One of the most important issues in network security analysis is voltage stability analysis. Due to the expected higher utilization of equipment induced by competition in a power market that covers bigger power systems, this issue is increasingly acute after deregulation. In this dissertation, some selected topics of voltage stability analysis are covered. In the first part, after a brief review of general concepts of continuation power flow (CPF), investigations on various matrix analysis techniques to improve the speed of CPF calculation for large systems are reported. Based on these improvements, a new CPF algorithm is proposed. This new method is then tested by an inter-area transaction in a large inter-connected power system. In the second part, the Arnoldi algorithm, the best method to find a few minimum singular values for a large sparse matrix, is introduced into the modal analysis for the first time. This new modal analysis is applied to the estimation of the point of voltage collapse and contingency evaluation in voltage security assessment. Simulations show that the new method is very efficient. In the third part, after transient voltage stability component models are investigated systematically, a novel system model for transient voltage stability analysis, which is a logical-algebraic-differential-difference equation (LADDE), is offered. As an example, TCSC (Thyristor controlled series capacitors) is addressed as a transient voltage stabilizing controller. After a TCSC transient voltage stability model is outlined, a new TCSC controller is proposed to enhance both fault related and load increasing related transient voltage stability. Its ability is proven by the simulation.

  8. The Empirical Analysis of The Deregulation in Oil Products Prices - Gasoline Prices and Demand

    Energy Technology Data Exchange (ETDEWEB)

    Na, I.G. [Korea Energy Economics Institute, Euiwang (Korea)

    2001-11-01

    The deregulation in oil product prices started in 1997. This empirical study examines the effects of the deregulation on gasoline prices and gasoline demand. Major findings of this study are summarized as follows. First of all, no significant empirical evidence is found to support that the deregulation affects the determination of gasoline prices. Secondly, the effects of CIF crude oil price and exchange rate on gasoline prices seem to be consistent across different econometric models. The short-term CIF elasticity is estimated to be 0.13, while the short-term exchange rate elasticity is estimated to be 0.43. This finding implies that if CIF increases 10%, the gasoline prices increase 1.3%. For example, gasoline prices of 1,200won/liter increase 15.6 won/liter with 2$/bbl increase of 20$/bbl crude price. Thirdly, the hypothesis of asymmetric response to CIF rises and falls is examined. No evidence of asymmetric response is found. Finally, the effect of deregulation on gasoline demand is estimated. It is found that the elasticities of gasoline prices and income (GDP) were dramatically changed into elastic response between pre-deregulation period and post-deregulation period. The short-term gasoline price elasticity increases from -0.18 in pre-deregulation period to -0.99 in post-deregulation period while the short-term income elasticity changes from 0.15 to 0.39 over the same period. (author). 40 refs., 36 figs., 34 tabs.

  9. Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing

    DEFF Research Database (Denmark)

    Galanos, Panagiotis; Vougas, Konstantinos; Walter, David

    2016-01-01

    , leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery-an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some...

  10. Modification of the plasma complement protein profile by exogenous estrogens is indicative of a compromised immune competence in marine medaka (Oryzias melastigma).

    Science.gov (United States)

    Dong, Miao; Seemann, Frauke; Humble, Joseph L; Liang, Yimin; Peterson, Drew R; Ye, Rui; Ren, Honglin; Kim, Hui-Su; Lee, Jae-Seong; Au, Doris W T; Lam, Yun Wah

    2017-09-04

    Growing evidence suggests that the immune system of teleost is vulnerable to xenoestrogens, which are ubiquitous in the marine environment. This study detected and identified the major circulatory immune proteins deregulated by 17α-ethinylestradiol (EE2), which may be linked to fish susceptibility to pathogens in the marine medaka, Oryzias melastigma. Fish immune competence was determined using a host resistance assay to pathogenic bacteria Edwardsiella tarda. Females were consistently more susceptible to infection-induced mortality than males. Exposure to EE2 could narrow the sex gap of mortality by increasing infection-induced death in male fish. Proteomic analysis revealed that the major plasma immune proteins of adult fish were highly sexually dimorphic. EE2 induced pronounced sex-specific changes in the plasma proteome, with the male plasma composition clearly becoming "feminised". Male plasma was found to contain a higher level of fibrinogens, WAP63 and ependymin-2-like protein, which are involved in coagulation, inflammation and regeneration. For the first time, we demonstrated that expression of C1q subunit B (C1Q), an initiating factor of the classical complement pathway, was higher in males and was suppressed in both sexes in response to EE2 and bacterial challenge. Moreover, cleavage and post-translational modification of C3, the central component of the complement system, could be altered by EE2 treatment in males (C3dg down; C3g up). Multiple regression analysis indicated that C1Q is possibly an indicator of fish survival, which warrants further confirmation. The findings support the potential application of plasma immune proteins for prognosis/diagnosis of fish immune competence. Moreover, this study provides the first biochemical basis of the sex-differences in fish immunity and how these differences might be modified by xenoestrogens. Copyright © 2017. Published by Elsevier Ltd.

  11. Deregulation of DNA double-strand break repair in multiple myeloma: implications for genome stability.

    Directory of Open Access Journals (Sweden)

    Ana B Herrero

    Full Text Available Multiple myeloma (MM is a hematological malignancy characterized by frequent chromosome abnormalities. However, the molecular basis for this genome instability remains unknown. Since both impaired and hyperactive double strand break (DSB repair pathways can result in DNA rearrangements, we investigated the functionality of DSB repair in MM cells. Repair kinetics of ionizing-radiation (IR-induced DSBs was similar in MM and normal control lymphoblastoid cell lines, as revealed by the comet assay. However, four out of seven MM cell lines analyzed exhibited a subset of persistent DSBs, marked by γ-H2AX and Rad51 foci that elicited a prolonged G2/M DNA damage checkpoint activation and hypersensitivity to IR, especially in the presence of checkpoint inhibitors. An analysis of the proteins involved in DSB repair in MM cells revealed upregulation of DNA-PKcs, Artemis and XRCC4, that participate in non-homologous end joining (NHEJ, and Rad51, involved in homologous recombination (HR. Accordingly, activity of both NHEJ and HR were elevated in MM cells compared to controls, as determined by in vivo functional assays. Interestingly, levels of proteins involved in a highly mutagenic, translocation-promoting, alternative NHEJ subpathway (Alt-NHEJ were also increased in all MM cell lines, with the Alt-NHEJ protein DNA ligase IIIα, also overexpressed in several plasma cell samples isolated from MM patients. Overactivation of the Alt-NHEJ pathway was revealed in MM cells by larger deletions and higher sequence microhomology at repair junctions, which were reduced by chemical inhibition of the pathway. Taken together, our results uncover a deregulated DSB repair in MM that might underlie the characteristic genome instability of the disease, and could be therapeutically exploited.

  12. Complement C3c as a Biomarker in Heart Failure

    Directory of Open Access Journals (Sweden)

    A. Frey

    2013-01-01

    Full Text Available Introduction. Experimental data indicates an important role of the innate immune system in cardiac remodeling and heart failure (HF. Complement is a central effector pathway of the innate immune system. Animals lacking parts of the complement system are protected from adverse remodeling. Based on these data, we hypothesized that peripheral complement levels could be a good marker for adverse remodeling and prognosis in patients with HF. Methods and Results. Since complement activation converges on the complement factor C3, we measured serum C3c, a stable C3-conversion product, in 197 patients with stable systolic HF. Subgroups with normal and elevated C3c levels were compared. C3c levels were elevated in 17% of the cohort. Patients with elevated C3c levels exhibited a trend to better survival, slightly higher LVEF, and lower NTpro-BNP values in comparison to patients with normal C3c values. No differences were found regarding NYHA functional class. Significantly more patients with elevated C3c had preexisting diabetes. The prevalence of CAD, arterial hypertension, and atrial fibrillation was not increased in patients with elevated C3c. Conclusion. Elevated C3c levels are associated with less adverse remodeling and improved survival in patients with stable systolic heart failure.

  13. Coagulation and complement system in critically ill patients.

    Science.gov (United States)

    Helling, H; Stephan, B; Pindur, G

    2015-01-01

    Activation of coagulation and inflammatory response including the complement system play a major role in the pathogenesis of critical illness. However, only limited data are available addressing the relationship of both pathways and its assessment of a predictive value for the clinical outcome in intense care medicine. Therefore, parameters of the coagulation and complement system were studied in patients with septicaemia and multiple trauma regarded as being exemplary for critical illness. 34 patients (mean age: 51.38 years (±16.57), 15 females, 19 males) were investigated at day 1 of admittance to the intensive care unit (ICU). Leukocytes, complement factors C3a and C5a were significantly (p complement system as part of the inflammatory response is a significant mechanism in septicaemia, whereas loss and consumption of blood components including parts of the coagulation and complement system is more characteristic for multiple trauma. Protein C in case of severe reduction might be of special concern for surviving in sepsis. Activation of haemostasis was occurring in both diseases, however, overt DIC was not confirmed in this study to be a leading mechanism in critically ill patients. MOF score, lactate, C1-inhibitor and prothrombin time have been the only statistically significant predictors for lethal outcome suggesting that organ function, microcirculation, haemostasis and inflammatory response are essential elements of the pathomechanism and clinical course of diseases among critically ill patients.

  14. Function of Serum Complement in Drinking Water Arsenic Toxicity

    Directory of Open Access Journals (Sweden)

    Laila N. Islam

    2012-01-01

    Full Text Available Serum complement function was evaluated in 125 affected subjects suffering from drinking water arsenic toxicity. Their mean duration of exposure was 7.4±5.3 yrs, and the levels of arsenic in drinking water and urine samples were 216±211 and 223±302 μg/L, respectively. The mean bactericidal activity of complement from the arsenic patients was 92% and that in the unexposed controls was 99% (P<0.01, but heat-inactivated serum showed slightly elevated activity than in controls. In patients, the mean complement C3 was 1.56 g/L, and C4 was 0.29 g/L compared to 1.68 g/L and 0.25 g/L, respectively, in the controls. The mean IgG in the arsenic patients was 24.3 g/L that was highly significantly elevated (P<0.001. Arsenic patients showed a significant direct correlation between C3 and bactericidal activity (P=0.014. Elevated levels of C4 indicated underutilization and possibly impaired activity of the classical complement pathway. We conclude reduced function of serum complement in drinking water arsenic toxicity.

  15. Complement Biomarkers as Predictors of Disease Progression in Alzheimer's Disease.

    Science.gov (United States)

    Hakobyan, Svetlana; Harding, Katharine; Aiyaz, Mohammed; Hye, Abdul; Dobson, Richard; Baird, Alison; Liu, Benjamine; Harris, Claire Louise; Lovestone, Simon; Morgan, Bryan Paul

    2016-09-06

    There is a critical unmet need for reliable markers of disease and disease course in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). The growing appreciation of the importance of inflammation in early AD has focused attention on inflammatory biomarkers in cerebrospinal fluid or plasma; however, non-specific inflammation markers have disappointed to date. We have adopted a targeted approach, centered on an inflammatory pathway already implicated in the disease. Complement, a core system in innate immune defense and potent driver of inflammation, has been implicated in pathogenesis of AD based on a confluence of genetic, histochemical, and model data. Numerous studies have suggested that measurement of individual complement proteins or activation products in cerebrospinal fluid or plasma is useful in diagnosis, prediction, or stratification, but few have been replicated. Here we apply a novel multiplex assay to measure five complement proteins and four activation products in plasma from donors with MCI, AD, and controls. Only one complement analyte, clusterin, differed significantly between control and AD plasma (controls, 295 mg/l; AD, 388 mg/l: p converted to dementia one year later compared to non-converters; a model combining these three analytes with informative co-variables was highly predictive of conversion. The data confirm the relevance of complement biomarkers in MCI and AD and build the case for using multi-parameter models for disease prediction and stratification.

  16. Herbal complement inhibitors in the treatment of neuroinflammation: future strategy for neuroprotection.

    Science.gov (United States)

    Kulkarni, Amod P; Kellaway, Laurie A; Kotwal, Girish J

    2005-11-01

    The upregulated complement system plays a damaging role in disorders of the central nervous system (CNS). The classical and alternate pathways are two major pathways activated in neuroinflammatory disorders such as Alzheimer's disease, multiple sclerosis, traumatic brain injury, spinal cord injury, HIV-associated dementia, Parkinson's disease, and mad cow disease. Failure of currently available anti-inflammatory agents, especially cyclooxygenase inhibitors, in offering significant neuroprotection in large epidemiologic clinical trials of CNS disorders suggests an urgent need for the development of new neuroprotective agents. The positive preclinical outcomes in treating CNS disorders by complement regulatory molecules, such as vaccinia virus complement control protein, suggest the possibility of using complement-inhibitory molecules as neuroprotective agents. Several active ingredients of herbal origin are found to have complement-inhibitory activity. These herbal ingredients along with other anti-inflammatory roles might be useful in treating neuroinflammation associated with CNS disorders. Active ingredients of herbal origin with complement inhibitory ingredients are summarized and classified according to their chemical nature and specificity towards the major pathways activating the complement system. The structure activity relationship of some specific examples is also discussed in this report. This information might be helpful in formulating a natural panacea against complement-mediated neuroinflammation.

  17. Complement System Part I – Molecular Mechanisms of Activation and Regulation

    Science.gov (United States)

    Merle, Nicolas S.; Church, Sarah Elizabeth; Fremeaux-Bacchi, Veronique; Roumenina, Lubka T.

    2015-01-01

    Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals. The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage. Here, we discuss the recent advances describing the molecular and structural basis of activation and regulation of the complement pathways and their implication on physiology and pathology. This article will review the mechanisms of activation of alternative, classical, and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins, and the membrane-attack-complex. We will also discuss the importance of structure–function relationships using the example of atypical hemolytic uremic syndrome. Lastly, we will discuss the development and benefits of therapies using complement inhibitors. PMID:26082779

  18. Complement activation in experimental human malaria infection.

    NARCIS (Netherlands)

    Roestenberg, M.; McCall, M.B.B.; Mollnes, T.E.; Deuren, M. van; Sprong, T.; Klasen, I.S.; Hermsen, C.C.; Sauerwein, R.W.; Ven, A.J.A.M. van der

    2007-01-01

    The objective of this study was to investigate complement activation in uncomplicated, early phases of human malaria. Fifteen healthy volunteers were experimentally infected with Plasmodium falciparum malaria. Parasitemia and complement activation products were assessed. During blood stage parasitem

  19. Complements and the Wound Healing Cascade: An Updated Review

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    Hani Sinno

    2013-01-01

    Full Text Available Wound healing is a complex pathway of regulated reactions and cellular infiltrates. The mechanisms at play have been thoroughly studied but there is much still to learn. The health care system in the USA alone spends on average 9 billion dollars annually on treating of wounds. To help reduce patient morbidity and mortality related to abnormal or prolonged skin healing, an updated review and understanding of wound healing is essential. Recent works have helped shape the multistep process in wound healing and introduced various growth factors that can augment this process. The complement cascade has been shown to have a role in inflammation and has only recently been shown to augment wound healing. In this review, we have outlined the biology of wound healing and discussed the use of growth factors and the role of complements in this intricate pathway.

  20. Vaccinia complement control protein: Multi-functional protein and a potential wonder drug

    Indian Academy of Sciences (India)

    Purushottam Jha; Girish J Kotwal

    2003-04-01

    Vaccinia virus complement control protein (VCP) was one of the first viral molecules demonstrated to have a role in blocking complement and hence in the evasion of host defense. Structurally it is very similar to the human C4b-BP and the other members of complement control protein. Functionally it is most similar to the CR1 protein. VCP blocks both major pathways of complement activation. The crystal structure of VCP was determined a little over a year ago and it is the only known structure of an intact and complete complement control protein. In addition to binding complement, VCP also binds to heparin. These two binding abilities can take place simultaneously and contribute to its many function and to its potential use in several inflammatory diseases, e.g. Alzheimer’s disease (AD), CNS injury, xenotransplantation, etc. making it a truly fascinating molecule and potential drug.

  1. ON COMPLEMENTED SUBGROUPS OF FINITE GROUPS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    A subgroup H of a finite group G is said to be complemented in G if there exists a subgroup K of G such that G = HK and H ∩ K = 1. In this case, K is called a complement of H in G.In this note some results on complemented subgroups of finite groups are obtained.

  2. Complement in the Homeostatic and Ischemic Brain

    Science.gov (United States)

    Alawieh, Ali; Elvington, Andrew; Tomlinson, Stephen

    2015-01-01

    The complement system is a component of the immune system involved in both recognition and response to pathogens, and it is implicated in an increasing number of homeostatic and disease processes. It is well documented that reperfusion of ischemic tissue results in complement activation and an inflammatory response that causes post-reperfusion injury. This occurs following cerebral ischemia and reperfusion and triggers secondary damage that extends beyond the initial infarcted area, an outcome that has rationalized the use of complement inhibitors as candidate therapeutics after stroke. In the central nervous system, however, recent studies have revealed that complement also has essential roles in synaptic pruning, neurogenesis, and neuronal migration. In the context of recovery after stroke, these apparent divergent functions of complement may account for findings that the protective effect of complement inhibition in the acute phase after stroke is not always maintained in the subacute and chronic phases. The development of effective stroke therapies based on modulation of the complement system will require a detailed understanding of complement-dependent processes in both early neurodegenerative events and delayed neuro-reparatory processes. Here, we review the role of complement in normal brain physiology, the events initiating complement activation after cerebral ischemia-reperfusion injury, and the contribution of complement to both injury and recovery. We also discuss how the design of future experiments may better characterize the dual role of complement in recovery after ischemic stroke. PMID:26322048

  3. A deregulated immune response to gliadin causes a decreased villus height in DQ8 transgenic mice.

    Science.gov (United States)

    D'Arienzo, Rossana; Stefanile, Rosita; Maurano, Francesco; Luongo, Diomira; Bergamo, Paolo; Mazzarella, Giuseppe; Troncone, Riccardo; Auricchio, Salvatore; David, Chella; Rossi, Mauro

    2009-12-01

    Celiac disease (CD) is an enteropathy triggered by gluten and mediated by CD4+ T cells. A complete understanding of CD immunopathogenesis has been hindered due to the lack of adequate in vivo models. Here, we explored the effect of the inhibition of COX by indomethacin in wheat gliadin-sensitized transgenic mice expressing the HLA-DQ8 heterodimer, a molecule associated with CD. Treated mice showed a gliadin-specific immune response with a significant reduction of villus height, not linked to crypt hyperplasia and to expansion of intraepithelial T cells. Notably, treated mice showed increased numbers of CD25+ and apoptotic cells in the lamina propria, whereas high basal levels of IFN-gamma secretion, along with a reduced gliadin-specific IL-2 expression were detected in MLN. Biochemical assessment of the lesion revealed increased mRNA of Lamb3 and Adamts2, encoding for ECM proteins, and enhanced activities of metalloproteinases MMP1, 2 and 7. We conclude that an intestinal sensitivity to gliadin, in connection with COX inhibition, caused a decreased villus height in DQ8 tg mice. The lesion was induced by a deregulated mucosal cell immunity to gliadin, thus triggering activation of a specific ECM protein pathway responsible for lamina propria remodeling.

  4. Hypoxanthine deregulates genes involved in early neuronal development. Implications in Lesch-Nyhan disease pathogenesis.

    Science.gov (United States)

    Torres, R J; Puig, J G

    2015-11-01

    Neurological manifestations in Lesch-Nyhan disease (LND) are attributed to the effect of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency on the nervous system development. HPRT deficiency causes the excretion of increased amounts of hypoxanthine into the extracellular medium and we hypothesized that HPRT deficiency related to hypoxanthine excess may then lead, directly or indirectly, to transcriptional aberrations in a variety of genes essential for the function and development of striatal progenitor cells. We have examined the effect of hypoxanthine excess on the differentiation of neurons in the well-established human NTERA-2 cl.D1 (NT2/D1) embryonic carcinoma neurogenesis model. NT2/D1 cells differentiate along neuroectodermal lineages after exposure to retinoic acid (RA). Hypoxanthine effects on RA-differentiation were examined by the changes on the expression of various transcription factor genes essential to neuronal differentiation and by the changes in tyrosine hydroxylase (TH), dopamine, adenosine and serotonin receptors (DRD, ADORA, HTR). We report that hypoxanthine excess deregulate WNT4, from Wnt/β-catenin pathway, and engrailed homeobox 1 gene and increased TH and dopamine DRD1, adenosine ADORA2A and serotonin HTR7 receptors, whose over expression characterize early neuro-developmental processes.

  5. Low level genome mistranslations deregulate the transcriptome and translatome and generate proteotoxic stress in yeast

    Directory of Open Access Journals (Sweden)

    Paredes João A

    2012-06-01

    Full Text Available Abstract Background Organisms use highly accurate molecular processes to transcribe their genes and a variety of mRNA quality control and ribosome proofreading mechanisms to maintain intact the fidelity of genetic information flow. Despite this, low level gene translational errors induced by mutations and environmental factors cause neurodegeneration and premature death in mice and mitochondrial disorders in humans. Paradoxically, such errors can generate advantageous phenotypic diversity in fungi and bacteria through poorly understood molecular processes. Results In order to clarify the biological relevance of gene translational errors we have engineered codon misreading in yeast and used profiling of total and polysome-associated mRNAs, molecular and biochemical tools to characterize the recombinant cells. We demonstrate here that gene translational errors, which have negligible impact on yeast growth rate down-regulate protein synthesis, activate the unfolded protein response and environmental stress response pathways, and down-regulate chaperones linked to ribosomes. Conclusions We provide the first global view of transcriptional and post-transcriptional responses to global gene translational errors and we postulate that they cause gradual cell degeneration through synergistic effects of overloading protein quality control systems and deregulation of protein synthesis, but generate adaptive phenotypes in unicellular organisms through activation of stress cross-protection. We conclude that these genome wide gene translational infidelities can be degenerative or adaptive depending on cellular context and physiological condition.

  6. Overview of the developments in the domestic airline industry in South Africa since market deregulation

    Directory of Open Access Journals (Sweden)

    Rose Luke

    2013-05-01

    Full Text Available Deregulation or liberalisation of air transport has had major global impacts on the domestic air transport markets, with effects ranging from stimulation to changes in the structure and functioning of these markets. In South Africa, deregulation has had wide-reaching effects on the domestic market. The purpose of this article was to investigate the current domestic air transport market. A literature review was performed to examine the effects of deregulation in other domestic air transport markets around the world. This was followed by a review of the South African domestic air transport market prior to deregulation in order to determine the changes that were made following deregulation. The ten-year period immediately following deregulation was also examined; this period was characterised by relatively large numbers of market entries and exits. A database was obtained from the Airports Company South Africa; air traffic movements, passenger numbers and load factors were evaluated. The study showed that the market is still characterised by regular market entries and exits. Also that the entry of the low-cost carriers has stimulated the market, resulting in increased air traffic movements, higher passenger numbers, higher load factors in general and the opening of a secondary airport in Gauteng, Lanseria International. Deregulation and, more specifically, the entry of the low-cost carriers has resulted in structural changes in the market and more choice for passengers.

  7. The Complement System: A Prey of Trypanosoma cruzi

    Directory of Open Access Journals (Sweden)

    Kárita C. F. Lidani

    2017-04-01

    Full Text Available Trypanosoma cruzi is a protozoan parasite known to cause Chagas disease (CD, a neglected sickness that affects around 6–8 million people worldwide. Originally, CD was mainly found in Latin America but more recently, it has been spread to countries in North America, Asia, and Europe due the international migration from endemic areas. Thus, at present CD represents an important concern of global public health. Most of individuals that are infected by T. cruzi may remain in asymptomatic form all lifelong, but up to 40% of them will develop cardiomyopathy, digestive mega syndromes, or both. The interaction between the T. cruzi infective forms and host-related immune factors represents a key point for a better understanding of the physiopathology of CD. In this context, the complement, as one of the first line of host defense against infection was shown to play an important role in recognizing T. cruzi metacyclic trypomastigotes and in controlling parasite invasion. The complement consists of at least 35 or more plasma proteins and cell surface receptors/regulators, which can be activated by three pathways: classical (CP, lectin (LP, and alternative (AP. The CP and LP are mainly initiated by immune complexes or pathogen-associated molecular patterns (PAMPs, respectively, whereas AP is spontaneously activated by hydrolysis of C3. Once activated, several relevant complement functions are generated which include opsonization and phagocytosis of particles or microorganisms and cell lysis. An important step during T. cruzi infection is when intracellular trypomastigotes are release to bloodstream where they may be target by complement. Nevertheless, the parasite uses a sequence of events in order to escape from complement-mediated lysis. In fact, several T. cruzi molecules are known to interfere in the initiation of all three pathways and in the assembly of C3 convertase, a key step in the activation of complement. Moreover, T. cruzi promotes secretion

  8. A pathogenic role of complement in arterial hypertension and hypertensive end organ damage.

    Science.gov (United States)

    Wenzel, Ulrich O; Bode, Marlies; Köhl, Jörg; Ehmke, Heimo

    2017-03-01

    The self-amplifying cascade of messenger and effector molecules of the complement system serves as a powerful danger-sensing system that protects the host from a hostile microbial environment, while maintaining proper tissue and organ function through effective clearance of altered or dying cells. As an important effector arm of innate immunity, it also plays important roles in the regulation of adaptive immunity. Innate and adaptive immune responses have been identified as crucial players in the pathogenesis of arterial hypertension and hypertensive end organ damage. In line with this view, complement activation may drive the pathology of hypertension and hypertensive injury through its impact on innate and adaptive immune responses. It is well known that complement activation can cause tissue inflammation and injury and complement-inhibitory drugs are effective treatments for several inflammatory diseases. In addition to these proinflammatory properties, complement cleavage fragments of C3 and C5 can exert anti-inflammatory effects that dampen the inflammatory response to injury. Recent experimental data strongly support a role for complement in arterial hypertension. The remarkably similar clinical and histopathological features of malignant nephrosclerosis and atypical hemolytic uremic syndrome, which is driven by complement activation, suggest a role for complement also in the development of malignant nephrosclerosis. Herein, we will review canonical and noncanonical pathways of complement activation as the framework to understand the multiple roles of complement in arterial hypertension and hypertensive end organ damage.

  9. Using animal models to determine the significance of complement activation in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Loeffler David A

    2004-10-01

    Full Text Available Abstract Complement inflammation is a major inflammatory mechanism whose function is to promote the removal of microorganisms and the processing of immune complexes. Numerous studies have provided evidence for an increase in this process in areas of pathology in the Alzheimer's disease (AD brain. Because complement activation proteins have been demonstrated in vitro to exert both neuroprotective and neurotoxic effects, the significance of this process in the development and progression of AD is unclear. Studies in animal models of AD, in which brain complement activation can be experimentally altered, should be of value for clarifying this issue. However, surprisingly little is known about complement activation in the transgenic animal models that are popular for studying this disorder. An optimal animal model for studying the significance of complement activation on Alzheimer's – related neuropathology should have complete complement activation associated with senile plaques, neurofibrillary tangles (if present, and dystrophic neurites. Other desirable features include both classical and alternative pathway activation, increased neuronal synthesis of native complement proteins, and evidence for an increase in complement activation prior to the development of extensive pathology. In order to determine the suitability of different animal models for studying the role of complement activation in AD, the extent of complement activation and its association with neuropathology in these models must be understood.

  10. Complement inhibiting properties of dragon's blood from Croton draco.

    Science.gov (United States)

    Tsacheva, Ivanka; Rostan, Joerg; Iossifova, Tania; Vogler, Bernhard; Odjakova, Mariela; Navas, Hernan; Kostova, Ivanka; Kojouharova, Michaela; Kraus, Wolfgang

    2004-01-01

    The latex of Croton draco, its extracts and several latex components have been investigated for their influence on both classical (CP) and alternative (AP) activation pathways of the complement system using a hemolytic assay. The best inhibition was found for the classical pathway. The latex, ethyl acetate and ethyl ether extracts exhibited extremely high inhibition on the CP (94, 90 and 77%, respectively) at a concentration of 1 mg/ml. The flavonoid myricitrin, the alkaloid taspine and the cyclopeptides P1 and P2 showed high inhibition on CP (83, 91, 78 and 63%, respectively) at a concentration of 0.9 mM.

  11. Complement the hemostatic system: an intimate relationship.

    Science.gov (United States)

    Weitz, Ilene Ceil

    2014-05-01

    The complement system is important part of our innate immune system and interacts directly with the hemostatic system. Disorders of complement activation or dysregulation resulting in excess complement generation, such as Paroxysmal Nocturnal Hemoglobinuria (PNH), atypical Hemolytic uremic Syndrome (aHUS) and antiphospholipid syndrome (APLS) have been associated with significant thrombophilia. Terminal Complement (C5b-9) deposition on endothelial and tumor cell membranes has also been reported in a variety of cancer. Recent developments in complement inhibition have given us new insights into the mechanism of thrombosis in these disorders.

  12. The Complement System in Liver Diseases

    Institute of Scientific and Technical Information of China (English)

    Xuebin Qin; Bin Gao

    2006-01-01

    The complement system plays an important role in mediating both acquired and innate responses to defend against microbial infection, and in disposing immunoglobins and apoptotic cells. The liver (mainly hepatocytes) is responsible for biosynthesis of about 80-90% of plasma complement components and expresses a variety of complement receptors.Recent evidence from several studies suggests that the complement system is also involved in the pathogenesis of a variety of liver disorders including liver injury and repair, fibrosis, viral hepatitis, alcoholic liver disease, and liver ischemia/reperfusion injury. In this review, we will discuss the potential role of the complement system in the pathogenesis of liver diseases.

  13. Complement-activated oligodendroglia: a new pathogenic entity identified by immunostaining with antibodies to human complement proteins C3d and C4d.

    Science.gov (United States)

    Yamada, T; Akiyama, H; McGeer, P L

    1990-05-04

    Clusters of oligodendroglial fibers were identified immunohistochemically in human brain tissue with antibodies to the complement proteins C3d and C4d in several neurological disorders. These included Pick's, Huntington's, Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy and Shy-Drager syndrome. These complement-activated oligodendroglia occurred in selected areas of gray and white matter. They were rarely observed in control tissue. Immunogold electron microscopy established that the C4d antibody was attached to degenerating myelin sheaths. These data indicate attachment of classical complement pathway proteins to selective oligodendroglia in several neurological disorders.

  14. Commercial banking in the conditions of deregulation vs. reregulation

    Directory of Open Access Journals (Sweden)

    Zaklan Damir

    2014-01-01

    Full Text Available This paper examines contemporary trends in commercial banking, confronting the stages of deregulation and reregulation in this field triggered by the global mortgage crisis. Under deregulatory conditions the competitive position of banks has toughened, and they reacted to it by intensifying: marketization, i.e. globalization, concentration, securitization and conglomeration, and by turning to the profit-oriented risk management of their activity. The contraction of their interest margin was thus neutralized by the reduction of operational costs and loss provisions, and by an increase in non-interest revenues, thereby maintaining banking profitability. The recent crisis has pinpointed the necessity of firmer regulation or reregulation of the banking sector, aimed at reducing its systemic risk, the most important aspect of which being the stricter international banking capital and liquidity standards, along with the requirement to adequately treat systemically important banks. Reregulation should strengthen capitalization and liquidity; mitigate the volume, concentration, internationalization and business dispersion, hence improving the supervision of the banking sector, implying its lower, yet more stable profitability. Such an impact of the adopted section of targeted regulatory measures has been indicated by higher liquidity, lower globalization, slower concentration and securitization, and stabilization-oriented risk management activities of today's banks. Their growth and profitability have shrunk.

  15. Issues in the deregulation of the electric industry

    Science.gov (United States)

    Tyler, Cleve Brent

    The electric industry is undergoing a major restructuring which allows competition in the generation portion of the industry. This dissertation explores several pricing issues relevant to this restructuring. First, an extensive overview examines the industry's history, discusses major regulation theories, and relays the major issues of deregulation. Second, a literature review recounts major works in the economics literature on price discrimination, pricing efficiency, and cost estimation. Then, customer specific generation, transmission, distribution, and general and administration costs are estimated for each company. The customer classes are residential, general service, large general service, and large industrial, representing a finer division of customer classes than found in previous studies. Average prices are compiled and marginal prices are determined from a set of utility schedules. Average and marginal price/cost ratios are computed for each customer class. These ratios show that larger use customers face relative price discrimination but operate under more efficient price structures than small use consumers. Finally, issues in peak load pricing are discussed using a model which predicts inefficient capital choice by regulated utilities. Efficiency losses are estimated to be $620 million dollars a year from the lack of peak load prices under regulation. This result is based on the time-of-use pricing predictions from the Department of Energy.

  16. Deregulation of dicer and mir-155 expression in liposarcoma

    Science.gov (United States)

    Vincenzi, Bruno; Iuliani, Michele; Zoccoli, Alice; Pantano, Francesco; Fioramonti, Marco; De Lisi, Delia; Frezza, Anna Maria; Rabitti, Carla; Perrone, Giuseppe; Muda, Andrea Onetti; Russo, Antonio; Giordano, Antonio; Santini, Daniele; Dei Tos, Angelo Paolo; Tonini, Giuseppe

    2015-01-01

    Liposarcoma (LPS) is the most common soft tissue sarcoma. It has been demonstrated that mir-155 was the most overexpressed miRNA in well-differentiated LPS(WDLPS)/dedifferentiated LPS (DDLPS). The aim of this study is to evaluate the involvement of Dicer, Drosha and mir-155 in development of LPS and their possible role in stratification of different histological subtypes. Dicer, Drosha and mir-155 mRNA levels were analyzed in formalin-fixed paraffin-embedded specimens from patients diagnosed with 62 LPS and compared with samples of adipose tissues of healthy donors. The experimental data were obtained using qRT-PCR comparing Dicer, Drosha and mir-155 expression levels in tumor samples versus normal fat. The tumor samples from LPS patients showed a significantly lower Dicer expression versus normal adipose tissue, while Drosha levels did not differ. Concerning mir155 expression levels, our results demonstrated a significant mir-155 up-regulation in all LPS subtypes versus normal adipose tissue except for WDLS. These findings demonstrate for the first time that Dicer is deregulated in LPS and show that mir-155 is differentially expressed in LPS subgroups and it could be a promising tool to improve LPS disease stratification and differential diagnosis. PMID:25888631

  17. Deregulation in the electricity sector: Understanding strategic and regulatory risk

    Energy Technology Data Exchange (ETDEWEB)

    Larsen, E.R. [City Univ. Business School, Dept. Management Systems and Information, London (United Kingdom); Bunn, D.W. [London Business School, London (United Kingdom)

    1999-08-01

    This paper is motivated by our experiences since 1990 with developing system simulation models to help UK companies in the restructured electricity industry understand the radically different market within which they must become competitive. When public utilities such as electricity have been restructured, deregulated and/or privatised, the process has often been associated with a major change in the competitive environment. As a consequence, the strategic and regulatory uncertainties ahead for these companies are unprecedented. In such a market there has been no historical evolution and all the participants including the regulatory institutions have very little understanding of how it will operate in the short term and evolve in the future. In this situation, the use of systems dynamic models appears to offer an attractive way of gaining insights into how aspects of the competitive market might evolve. In the absence of real experience and relevant analogies, learning from models assumes a key role. Such models cannot be validated empirically, but can be developed to represent how the system is designed to operate. From such a prototypical basis, sensitivity analysis can generate insights on the strategic opportunities created failings in the market design, or its potential instability to shocks and market imperfections. (au)

  18. Opportunities for privatization and alliances in a deregulated marketplace

    Energy Technology Data Exchange (ETDEWEB)

    Erling, J.M. [KPMG, Toronto, ON (Canada)

    1998-09-01

    The main implications for municipal electric utilities (MEUs) and businesses in a deregulated, open access energy market include a range of possible alternative business structures, constraints on choices, increased risks, the need to understand objectives, capabilities and capacity for bearing risks. The issue of what business MEUs are in, what services they provide and how those services should be delivered, was hotly debated. It was suggested that with increasing competition, the range of possible business structures and arrangements will widen significantly. The different public-private options available to MEUs are (1) the conventional tender process, (2) contracting out, (3) joint ventures with a private company, (4) franchising, (5) outsourcing of specific functions, (6) operating agreements, (7) lease arrangements, (8) build-operate-transfer options (BOTs), and (9) the full privatization scenario. It was noted that some forms of public-private partnerships are more suited to some businesses than others. Also, different partnership structures can be used in different parts of any business. Objectives for any partnership should include maximizing profitability, minimizing risk and promoting economic development but under competition. The ability to choose objectives will change significantly and the achievement of any of the objectives will be determined by the marketplace. Some guidelines on measuring success and on maximizing market value were offered. Global trends towards more unbundling and price transparency, more outsourcing to the private sector, more competition, less government, regulatory reform and blurring of the boundaries between utility sectors were predicted.

  19. Price-elastic demand in deregulated electricity markets

    Energy Technology Data Exchange (ETDEWEB)

    Siddiqui, Afzal S.

    2003-05-01

    The degree to which any deregulated market functions efficiently often depends on the ability of market agents to respond quickly to fluctuating conditions. Many restructured electricity markets, however, experience high prices caused by supply shortages and little demand-side response. We examine the implications for market operations when a risk-averse retailer's end-use consumers are allowed to perceive real-time variations in the electricity spot price. Using a market-equilibrium model, we find that price elasticity both increases the retailers revenue risk exposure and decreases the spot price. Since the latter induces the retailer to reduce forward electricity purchases, while the former has the opposite effect, the overall impact of price responsive demand on the relative magnitudes of its risk exposure and end-user price elasticity. Nevertheless, price elasticity decreases cumulative electricity consumption. By extending the analysis to allow for early settlement of demand, we find that forward stage end-user price responsiveness decreases the electricity forward price relative to the case with price-elastic demand only in real time. Moreover, we find that only if forward stage end-user demand is price elastic will the equilibrium electricity forward price be reduced.

  20. Deregulation and restructuring of the electric utility industry

    Energy Technology Data Exchange (ETDEWEB)

    Nixon, Hal [Utility Workers Union of America (UWUA), AFL-CIO, (United States)

    1997-12-31

    Federal and state policy makers are currently faced with the rapidly evolving issue of the restructuring and potential deregulation of the electric utility industry, a sector of the economy of huge importance through its sheer size and its impact on the daily life and livelihood of everyone. This paper describes eleven principles that must be adhered to in any restructuring of the electric industry. Adherence to the principle and positions outlined can help assure that the transition in this industry benefits all, not just a few, and that the general health and welfare of the people is protected and enhanced [Espanol] Los legisladores estatales y federales se estan enfrentando con el rapido y envolvente aspecto de la reestructuracion y desregulacion potencial de la industria electrica, un sector de la economia de enorme importancia por su tamano y su impacto en la vida diaria y los medios de vida. En esta ponencia se describen once principios y posiciones que deben ser considerados en cualquier reestructuracion de la industria electrica. El apego a los principios y posiciones comentados puede ayudar a asegurar que la transicion en esta industria deneficie a todos, no solo a unos cuantos, y que la salud general y bienestar de la gente sea protegida y mejorada

  1. The Semantics of Complementation in English: A Cognitive Semantic Account of Two English Complement Constructions

    Science.gov (United States)

    Smith, Michael B.

    2009-01-01

    Studies on complementation in English and other languages have traditionally focused on syntactic issues, most notably on the constituent structures of different complement types. As a result, they have neglected the role of meaning in the choice of different complements. This paper investigates the semantics of complementation within the…

  2. Immune response and mitochondrial metabolism are commonly deregulated in DMD and aging skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Daniel Baron

    Full Text Available Duchenne Muscular Dystrophy (DMD is a complex process involving multiple pathways downstream of the primary genetic insult leading to fatal muscle degeneration. Aging muscle is a multifactorial neuromuscular process characterized by impaired muscle regeneration leading to progressive atrophy. We hypothesized that these chronic atrophying situations may share specific myogenic adaptative responses at transcriptional level according to tissue remodeling. Muscle biopsies from four young DMD and four AGED subjects were referred to a group of seven muscle biopsies from young subjects without any neuromuscular disorder and explored through a dedicated expression microarray. We identified 528 differentially expressed genes (out of 2,745 analyzed, of which 328 could be validated by an exhaustive meta-analysis of public microarray datasets referring to DMD and Aging in skeletal muscle. Among the 328 validated co-expressed genes, 50% had the same expression profile in both groups and corresponded to immune/fibrosis responses and mitochondrial metabolism. Generalizing these observed meta-signatures with large compendia of public datasets reinforced our results as they could be also identified in other pathological processes and in diverse physiological conditions. Focusing on the common gene signatures in these two atrophying conditions, we observed enrichment in motifs for candidate transcription factors that may coordinate either the immune/fibrosis responses (ETS1, IRF1, NF1 or the mitochondrial metabolism (ESRRA. Deregulation in their expression could be responsible, at least in part, for the same transcriptome changes initiating the chronic muscle atrophy. This study suggests that distinct pathophysiological processes may share common gene responses and pathways related to specific transcription factors.

  3. Immune response and mitochondrial metabolism are commonly deregulated in DMD and aging skeletal muscle.

    Science.gov (United States)

    Baron, Daniel; Magot, Armelle; Ramstein, Gérard; Steenman, Marja; Fayet, Guillemette; Chevalier, Catherine; Jourdon, Philippe; Houlgatte, Rémi; Savagner, Frédérique; Pereon, Yann

    2011-01-01

    Duchenne Muscular Dystrophy (DMD) is a complex process involving multiple pathways downstream of the primary genetic insult leading to fatal muscle degeneration. Aging muscle is a multifactorial neuromuscular process characterized by impaired muscle regeneration leading to progressive atrophy. We hypothesized that these chronic atrophying situations may share specific myogenic adaptative responses at transcriptional level according to tissue remodeling. Muscle biopsies from four young DMD and four AGED subjects were referred to a group of seven muscle biopsies from young subjects without any neuromuscular disorder and explored through a dedicated expression microarray. We identified 528 differentially expressed genes (out of 2,745 analyzed), of which 328 could be validated by an exhaustive meta-analysis of public microarray datasets referring to DMD and Aging in skeletal muscle. Among the 328 validated co-expressed genes, 50% had the same expression profile in both groups and corresponded to immune/fibrosis responses and mitochondrial metabolism. Generalizing these observed meta-signatures with large compendia of public datasets reinforced our results as they could be also identified in other pathological processes and in diverse physiological conditions. Focusing on the common gene signatures in these two atrophying conditions, we observed enrichment in motifs for candidate transcription factors that may coordinate either the immune/fibrosis responses (ETS1, IRF1, NF1) or the mitochondrial metabolism (ESRRA). Deregulation in their expression could be responsible, at least in part, for the same transcriptome changes initiating the chronic muscle atrophy. This study suggests that distinct pathophysiological processes may share common gene responses and pathways related to specific transcription factors.

  4. MicroRNA-203-mediated posttranscriptional deregulation of CPEB4 contributes to colorectal cancer progression

    Energy Technology Data Exchange (ETDEWEB)

    Zhong, Xiaohua; Xiao, Yipin; Chen, Chao, E-mail: chenchaopw@126.com; Wei, Xiuwen; Hu, Chen; Ling, Xukun; Liu, Xinbin

    2015-10-16

    Elevated cytoplasmic polyadenylation element-binding 4 (CPEB4) is aberrantly expressed in several malignant cancers. However, its expression pattern, clinical significance, and biological function in colorectal cancer are still unknown. In this study, we demonstrated that CPEB4 is abundantly overexpressed in colorectal cancers and has the potential to be used for predicting clinical outcomes of colorectal cancer patients. We suppressed CPEB4 expression by small interfering RNA (siRNA) in SW480 and LOVO cells to clarify the role of CPEB4 on the cell apoptosis and proliferation in vitro. Further study revealed that knockdown of CPEB4 decreased the expression of anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL), but enhanced the expression of B-cell lymphoma-2-associated X (Bax). In addition, we indicated that CPEB4 is a novel target of miR-203, a tumor suppressive microRNA. Notably, restoration of CPEB4 in SW480 cells inhibited miR-203-induced apoptosis signaling pathway, which in turn enhanced cell proliferation and suppressed cell apoptosis. Taken together, our findings imply that posttranscriptional deregulation of CPEB4 contributes to the inhibited cell proliferation and the enhanced cell apoptosis in colorectal cancer, and directly targeting CPEB4 by miR-203 might be a novel strategy in colorectal cancer treatment. - Highlights: • CPEB4 is aberrantly expressed in human colorectal cancers. • Knockdown of CPEB4 inhibited colorectal cancer cell proliferation and enhanced apoptosis. • CPEB4 is a direct target of miR-203 and inversely correlates with miR-203 expression. • miR-203 inhibited cell growth and enhanced cell apoptosis in CPEB4 dependent manner. • miR-203 is an upstream regulator of the CPEB4-induced apoptosis pathway.

  5. Pre-exposure of Mycobacterium tuberculosis-infected macrophages to crystalline silica impairs control of bacterial growth by deregulating the balance between apoptosis and necrosis.

    Directory of Open Access Journals (Sweden)

    Leslie Chávez-Galán

    Full Text Available Inhalation of crystalline silica (CS particles increases the risk of pulmonary tuberculosis; however, the precise mechanism through which CS exposure facilitates Mycobacterium tuberculosis (Mtb infection is unclear. We speculate that macrophage exposure to CS deregulates the cell death pathways that could explain, at least in part, the association observed between exposure to CS and pulmonary tuberculosis. We therefore established an in vitro model in which macrophages were exposed to CS and then infected with Mtb. Expression of surface markers was analyzed by flow cytometry, JNK1/2, ASK1, caspase 9, P-p38, Bcl-2 and Mcl-1 were analyzed by Western blot, and cytokines by ELISA. Our results show that exposure to CS limits macrophage ability to control Mtb growth. Moreover, this exposure reduced the expression of TLR2, Bcl-2 and Mcl-1, but increased that of JNK1 and ASK1 molecules in the macrophages. Finally, when the pre-exposed macrophages were infected with Mtb, the concentrations of TNFα, IL-1β and caspase-9 expression increased. This pro-inflammatory profile of the macrophage unbalanced the apoptosis/necrosis pathway. Taken together, these data suggest that macrophages exposed to CS are sensitized to cell death by MAPK kinase-dependent signaling pathway. Secretion of TNF-α and IL-1β by Mtb-infected macrophages promotes necrosis, and this deregulation of cell death pathways may favor the release of viable bacilli, thus leading to the progression of tuberculosis.

  6. Microbes bind complement inhibitor factor H via a common site.

    Directory of Open Access Journals (Sweden)

    T Meri

    Full Text Available To cause infections microbes need to evade host defense systems, one of these being the evolutionarily old and important arm of innate immunity, the alternative pathway of complement. It can attack all kinds of targets and is tightly controlled in plasma and on host cells by plasma complement regulator factor H (FH. FH binds simultaneously to host cell surface structures such as heparin or glycosaminoglycans via domain 20 and to the main complement opsonin C3b via domain 19. Many pathogenic microbes protect themselves from complement by recruiting host FH. We analyzed how and why different microbes bind FH via domains 19-20 (FH19-20. We used a selection of FH19-20 point mutants to reveal the binding sites of several microbial proteins and whole microbes (Haemophilus influenzae, Bordetella pertussis, Pseudomonas aeruginosa, Streptococcus pneumonia, Candida albicans, Borrelia burgdorferi, and Borrelia hermsii. We show that all studied microbes use the same binding region located on one side of domain 20. Binding of FH to the microbial proteins was inhibited with heparin showing that the common microbial binding site overlaps with the heparin site needed for efficient binding of FH to host cells. Surprisingly, the microbial proteins enhanced binding of FH19-20 to C3b and down-regulation of complement activation. We show that this is caused by formation of a tripartite complex between the microbial protein, FH, and C3b. In this study we reveal that seven microbes representing different phyla utilize a common binding site on the domain 20 of FH for complement evasion. Binding via this site not only mimics the glycosaminoglycans of the host cells, but also enhances function of FH on the microbial surfaces via the novel mechanism of tripartite complex formation. This is a unique example of convergent evolution resulting in enhanced immune evasion of important pathogens via utilization of a "superevasion site."

  7. Hepatitis C virus NS3/4A protease inhibits complement activation by cleaving complement component 4.

    Directory of Open Access Journals (Sweden)

    Seiichi Mawatari

    Full Text Available BACKGROUND: It has been hypothesized that persistent hepatitis C virus (HCV infection is mediated in part by viral proteins that abrogate the host immune response, including the complement system, but the precise mechanisms are not well understood. We investigated whether HCV proteins are involved in the fragmentation of complement component 4 (C4, composed of subunits C4α, C4β, and C4γ, and the role of HCV proteins in complement activation. METHODS: Human C4 was incubated with HCV nonstructural (NS 3/4A protease, core, or NS5. Samples were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and then subjected to peptide sequencing. The activity of the classical complement pathway was examined using an erythrocyte hemolysis assay. The cleavage pattern of C4 in NS3/4A-expressing and HCV-infected cells, respectively, was also examined. RESULTS: HCV NS3/4A protease cleaved C4γ in a concentration-dependent manner, but viral core and NS5 did not. A specific inhibitor of NS3/4A protease reduced C4γ cleavage. NS3/4A protease-mediated cleavage of C4 inhibited classical pathway activation, which was abrogated by a NS3/4A protease inhibitor. In addition, co-transfection of cells with C4 and wild-type NS3/4A, but not a catalytic-site mutant of NS3/4A, produced cleaved C4γ fragments. Such C4 processing, with a concomitant reduction in levels of full-length C4γ, was also observed in HCV-infected cells expressing C4. CONCLUSIONS: C4 is a novel cellular substrate of the HCV NS3/4A protease. Understanding disturbances in the complement system mediated by NS3/4A protease may provide new insights into the mechanisms underlying persistent HCV infection.

  8. Effects of the Deregulation on the Concentration of the Brazilian Air Transportation Industry

    Science.gov (United States)

    Guterres, Marcelo Xavier; Muller, Carlos

    2003-01-01

    This paper addresses the effects of the deregulation of the Brazilian air transportation industry in terms of the concentration of the market. We will show some metrics that are commonly used to study the concentration of the industry. This paper uses the Herfindhal- Hirschman Index. This index tends to zero in the competitive scenario, with a large number of small firms, and to one in case of a monopolistic scenario. The paper analyses the dynamics of the concentration of the Brazilian domestic air transportation market, in order to evaluate the effects of deregulation. We conclude that the Brazilian market presents oligopoly characteristics and aspects in its current structure that maintain the market concentrated in spite of the Deregulation measures adopted by the aeronautical authority. Keywords: Herfindhal-Hirschman Index, concentration, Deregulation

  9. Deregulation of the RB pathway in human testicular germ cell tumours

    DEFF Research Database (Denmark)

    Bartkova, Jirina; Lukas, Claudia; Sørensen, Claus S

    2003-01-01

    RB was expressed throughout adult spermatogenesis and was detectable in teratomas, but was absent or grossly reduced in carcinoma in situ (CIS) and most seminomas and embryonal carcinomas. Unexpectedly, we also found that pRB was absent from fetal human gonocytes, the candidate target cell for all types of TGCTs...

  10. TECHNOLOGY MANAGEMENT IN THE DEREGULATED ELECTRICITY DISTRIBUTION INDUSTRY: THE SOUTH AFRICAN CASE

    Directory of Open Access Journals (Sweden)

    M.G.B. Madonsela

    2012-01-01

    Full Text Available

    ENGLISH ABSTRACT: The subject of deregulation of electricity utilities has, in the past two decades, dominated the discussions on global Electricity Supply Industries (ESIs. Deregulation may be viewed as the withdrawal of state regulatory powers from the generation, transmission and distribution of electrical power to facilitate liberalised power markets. The key drivers for deregulation in South Africa are global competitiveness; a quest for local industrial development through cost-effective services; equitable and sustainable power supplies and the social empowerment of communities through the eradication of poverty. The present Electricity Distribution Industry (EDI, which is a component of the ESI, is made up of Eskom Distribution and about 368 municipal distributors. At present, both these entities run their businesses according to differing “business” principles. With technology being one of the driving forces of economic growth, this article analyses the deregulated EDI and proposes a technology management model that can be adopted after deregulation.

    AFRIKAANSE OPSOMMING: Gedurende die afgelope twee dekades oorheers die deregulering van elektrisiteitsvoorsiening besprekings oor die globale voorsiening van elektrisiteit. Deregulering beteken die verwydering van staatsbeheer oor die opwekking, transmissie en verspreiding van elektrisiteit om sodoende geliberaliseerde drywingsmarkte te ondersteun. Die aansporing vir deregulering in Suid-Afrika gaan om globale mededingendheid, om ondersteuning vir die ontwikkeling van plaaslike industrieë deur koste-effektiewe dienslewering, en om die voorsiening van gangbare en volhoubare kragbronne vir die bemagtiging van gemeenskappe vir die bekamping van armoede. Tans bestaan die elektriesiteitsverspreidingsbedryf uit Eskom-verspreiding en ongeveer 368 munisipale verspreiders. Hierdie samestelling maak onderling gebruik van uiteenlopende sakebeginsels. Hierdie artikel hou 'n tegnologiese

  11. Maize and wheat production trends in South Africa in a deregulated environment

    OpenAIRE

    Breitenbach, Marthinus C.; Fenyes, Tamas I.

    2000-01-01

    Qualitative control measures and government regulation of the marketing of agricultural produce was seen as distorting the working of the market mechanism. Trade liberalisation, with tariffication of agricultural produce and the deregulation of the marketing of agricultural produce was therefore promoted. It was expected that producers of agricultural produce would respond to liberalisation efforts and deregulation in a way that would move production closer to some optimum point. An analysis ...

  12. Power shift: a media analysis of the discourse of electricity deregulation in British Columbia

    OpenAIRE

    Simmons, Gregory Nigel

    2008-01-01

    Despite a record of low rates and significant public revenue generation on the part of the public utility, BC Hydro, the government of British Columbia in recent years has begun to deregulate the provincial electricity system. Measures undertaken include breaking up the utility and transferring responsibility for new generation to the private sector. I provide a content analysis of the process of electricity deregulation in British Columbia as represented in the Vancouver Sun and the Times Co...

  13. The Importance of Management in the Deregulated Retail Electricity Distribution Market in Slovenia

    OpenAIRE

    Drago Papler; Stefan Bojnec

    2006-01-01

    This paper underlines the importance of management in the deregulated retail electricity distribution market, entrepreneurship and business behaviours toward consumers’ satisfaction with quality of services. The coefficients of concentration indicate a high concentration of electricity suppliers and users in the deregulated electricity retail market for industry. The production function reveals the importance of education and electricity infrastructure, and to a lesser extent of capital inten...

  14. Evolutionary Programming Based Optimal Placement of UPFC Device in Deregulated Electricity Market

    OpenAIRE

    Balamurugan, K.; Dr. R. Muralisachithanandam; Dr. V. Dharmalingam; Mr. K. V. Sethuraman

    2014-01-01

    In deregulated power industry, the real time pricing of real power has an important issue to create fair open access and great impact of efficient and economics operation of deregulated electricity market. FACTS devices can be used to control the power flows. Therefore the optimal allocation of FACTS device can be used to achieve the optimal power flow without any constraints violation and thus to increase the utilization of the lowest cost generation in power system network. This paper propo...

  15. Deregulated Renal Calcium and Phosphate Transport during Experimental Kidney Failure.

    Science.gov (United States)

    Pulskens, Wilco P; Verkaik, Melissa; Sheedfar, Fareeba; van Loon, Ellen P; van de Sluis, Bart; Vervloet, Mark G; Hoenderop, Joost G; Bindels, René J

    2015-01-01

    Impaired mineral homeostasis and inflammation are hallmarks of chronic kidney disease (CKD), yet the underlying mechanisms of electrolyte regulation during CKD are still unclear. Here, we applied two different murine models, partial nephrectomy and adenine-enriched dietary intervention, to induce kidney failure and to investigate the subsequent impact on systemic and local renal factors involved in Ca(2+) and Pi regulation. Our results demonstrated that both experimental models induce features of CKD, as reflected by uremia, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL) expression. In our model kidney failure was associated with polyuria, hypercalcemia and elevated urinary Ca(2+) excretion. In accordance, CKD augmented systemic PTH and affected the FGF23-αklotho-vitamin-D axis by elevating circulatory FGF23 levels and reducing renal αklotho expression. Interestingly, renal FGF23 expression was also induced by inflammatory stimuli directly. Renal expression of Cyp27b1, but not Cyp24a1, and blood levels of 1,25-dihydroxy vitamin D3 were significantly elevated in both models. Furthermore, kidney failure was characterized by enhanced renal expression of the transient receptor potential cation channel subfamily V member 5 (TRPV5), calbindin-D28k, and sodium-dependent Pi transporter type 2b (NaPi2b), whereas the renal expression of sodium-dependent Pi transporter type 2a (NaPi2a) and type 3 (PIT2) were reduced. Together, our data indicates two different models of experimental kidney failure comparably associate with disturbed FGF23-αklotho-vitamin-D signalling and a deregulated electrolyte homeostasis. Moreover, this study identifies local tubular, possibly inflammation- or PTH- and/or FGF23-associated, adaptive mechanisms, impacting on Ca(2+)/Pi homeostasis, hence enabling new opportunities to target electrolyte disturbances that emerge as a consequence of CKD development.

  16. The deregulation connection : utility competition creates new niche company

    Energy Technology Data Exchange (ETDEWEB)

    Roy, C

    1999-08-01

    Deregulation in Ontario's utility market has created incentives for local utilities to add new services to attract and keep customers, knowing that in a competitive energy market, only those utilities which offer the best services will survive. London Hydro, which provides power to southwestern Ontario launched a private enterprise called LondonConnect Inc. The new enterprise offers high-speed digital services to area businesses. London Hydro made this unique move to take advantage of the fact that 20 per cent of businesses communicate electronically. London Hydro believes that in the next five years, that number will increase to 80 per cent. The Metropolitan Area Network (MAN) gives businesses greater connectivity to the Internet and web services. One of the network's capabilities is realtime video conferencing between hydro locations. MAN can also be used to create a secure and private virtual community-wide area network of computers and office machines. The advantages are numerous. For example, hospitals will be able to exchange information between remote sites at incredible speeds. MAN is made up of fiber-optic cables and electronic routers. LondonConnect is expecting to provide access throughout London by the fall of 1999. A dozen clients have already signed up for the service. Installation of the system will cost $1,000 with fixed monthly rates. The cost will vary depending on the level of service. The network will cost London Hydro $3 million, but it is expected to generate $2.5 million annually in its first two years. 3 figs.

  17. The deregulation connection : utility competition creates new niche company

    Energy Technology Data Exchange (ETDEWEB)

    Roy, C.

    1999-08-01

    Deregulation in Ontario`s utility market has created incentives for local utilities to add new services to attract and keep customers, knowing that in a competitive energy market, only those utilities which offer the best services will survive. London Hydro, which provides power to southwestern Ontario launched a private enterprise called LondonConnect Inc. The new enterprise offers high-speed digital services to area businesses. London Hydro made this unique move to take advantage of the fact that 20 per cent of businesses communicate electronically. London Hydro believes that in the next five years, that number will increase to 80 per cent. The Metropolitan Area Network (MAN) gives businesses greater connectivity to the Internet and web services. One of the network`s capabilities is realtime video conferencing between hydro locations. MAN can also be used to create a secure and private virtual community-wide area network of computers and office machines. The advantages are numerous. For example, hospitals will be able to exchange information between remote sites at incredible speeds. MAN is made up of fiber-optic cables and electronic routers. LondonConnect is expecting to provide access throughout London by the fall of 1999. A dozen clients have already signed up for the service. Installation of the system will cost $1,000 with fixed monthly rates. The cost will vary depending on the level of service. The network will cost London Hydro $3 million, but it is expected to generate $2.5 million annually in its first two years. 3 figs.

  18. Fuel, environmental, and transmission pricing considerations in a deregulated environment

    Science.gov (United States)

    Obessis, Emmanouil Vlassios

    The 1992 National Energy Policy Act drastically changed the traditional structure of the vertically integrated utility. To facilitate increased competition in the power utility sector, all markets related to power generation have been opened to free competition and trading. To survive in the new competitive environment, power producers need to reduce costs and increase efficiency. Fuel marketing strategies are thus, getting more aggressive and fuel markets are becoming more competitive, offering more options regarding fuel supplies and contracts. At the same time, the 1990 Clean Air Act Amendments are taking effect. Although tightening the emission standards, this legislation offers utilities a wider flexibility in choosing compliance strategies. It also set maximum annual allowable levels replacing the traditional uniform maximum emission rates. The bill also introduced the concept of marketable emission allowances and provided for the establishment of nationwide markets where allowances may be traded, sold, or purchased. Several fuel- and emission-constrained algorithms have been historically presented, but those two classes of constraints, in general, were handled independently. The multiobjective optimization model developed in this research work, concurrently satisfies sets of detailed fuel and emission limits, modeling in a more accurate way the fuel supply and environmental limitations and their complexities in the new deregulated operational environment. Development of the implementation software is an integral part of this research project. This software may be useful for both daily scheduling activities and short-term operational planning. A Lagrangian multipliers-based variant is used to solve the problem. Single line searches are used to update the multipliers, thus offering attractive execution times. This work also investigates the applicability of cooperative games to the problem of transmission cost allocation. Interest in game theory as a powerful

  19. Deregulated Renal Calcium and Phosphate Transport during Experimental Kidney Failure.

    Directory of Open Access Journals (Sweden)

    Wilco P Pulskens

    Full Text Available Impaired mineral homeostasis and inflammation are hallmarks of chronic kidney disease (CKD, yet the underlying mechanisms of electrolyte regulation during CKD are still unclear. Here, we applied two different murine models, partial nephrectomy and adenine-enriched dietary intervention, to induce kidney failure and to investigate the subsequent impact on systemic and local renal factors involved in Ca(2+ and Pi regulation. Our results demonstrated that both experimental models induce features of CKD, as reflected by uremia, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL expression. In our model kidney failure was associated with polyuria, hypercalcemia and elevated urinary Ca(2+ excretion. In accordance, CKD augmented systemic PTH and affected the FGF23-αklotho-vitamin-D axis by elevating circulatory FGF23 levels and reducing renal αklotho expression. Interestingly, renal FGF23 expression was also induced by inflammatory stimuli directly. Renal expression of Cyp27b1, but not Cyp24a1, and blood levels of 1,25-dihydroxy vitamin D3 were significantly elevated in both models. Furthermore, kidney failure was characterized by enhanced renal expression of the transient receptor potential cation channel subfamily V member 5 (TRPV5, calbindin-D28k, and sodium-dependent Pi transporter type 2b (NaPi2b, whereas the renal expression of sodium-dependent Pi transporter type 2a (NaPi2a and type 3 (PIT2 were reduced. Together, our data indicates two different models of experimental kidney failure comparably associate with disturbed FGF23-αklotho-vitamin-D signalling and a deregulated electrolyte homeostasis. Moreover, this study identifies local tubular, possibly inflammation- or PTH- and/or FGF23-associated, adaptive mechanisms, impacting on Ca(2+/Pi homeostasis, hence enabling new opportunities to target electrolyte disturbances that emerge as a consequence of CKD development.

  20. The role of complement activation in atherogenesis: the first 40 years.

    Science.gov (United States)

    Vlaicu, Sonia I; Tatomir, Alexandru; Rus, Violeta; Mekala, Armugam P; Mircea, Petru A; Niculescu, Florin; Rus, Horea

    2016-02-01

    The pathogenesis of atherosclerotic inflammation is a multi-step process defined by the interweaving of excess modified lipid particles, monocyte-macrophages populations, and innate immune and adaptive immunity effectors. A part of innate immunity, the complement system, is an important player in the induction and progression of atherosclerosis. The accumulation of either oxidized or enzymatically modified LDL-bound to C-reactive protein or not-prompts complement activation leading to the assembly of the terminal complement C5b-9 complex in the atherosclerotic lesion. The sublytic C5b-9 assembly leads to the activation and proliferation of smooth muscle and endothelial cells, accompanied by the release of various chemotactic, pro-adhesion, and procoagulant cytokines from these cells. Response gene to complement (RGC)-32, an essential effector of the terminal complement complex C5b-9, also affects atherogenesis, propelling vascular smooth muscle cell proliferation and migration, stimulating endothelial proliferation, and promoting vascular lesion formation. A substantial amount of experimental work has suggested a role for the complement system activation during atherosclerotic plaque formation, with the proximal classical complement pathway seemingly having a protective effect and terminal complement contributing to accelerated atherogenesis. All these data suggest that complement plays an important role in atherogenesis.

  1. Complement diagnostics: concepts, indications, and practical guidelines.

    Science.gov (United States)

    Nilsson, Bo; Ekdahl, Kristina Nilsson

    2012-01-01

    Aberrations in the complement system have been shown to be direct or indirect pathophysiological mechanisms in a number of diseases and pathological conditions such as autoimmune disease, infections, cancer, allogeneic and xenogeneic transplantation, and inflammation. Complement analyses have been performed on these conditions in both prospective and retrospective studies and significant differences have been found between groups of patients, but in many diseases, it has not been possible to make predictions for individual patients because of the lack of sensitivity and specificity of many of the assays used. The basic indications for serological diagnostic complement analysis today may be divided into three major categories: (a) acquired and inherited complement deficiencies; (b) disorders with complement activation; (c) inherited and acquired C1INH deficiencies. Here, we summarize indications, techniques, and interpretations for basic complement analyses and present an algorithm, which we follow in our routine laboratory.

  2. Complement Diagnostics: Concepts, Indications, and Practical Guidelines

    Directory of Open Access Journals (Sweden)

    Bo Nilsson

    2012-01-01

    Full Text Available Aberrations in the complement system have been shown to be direct or indirect pathophysiological mechanisms in a number of diseases and pathological conditions such as autoimmune disease, infections, cancer, allogeneic and xenogeneic transplantation, and inflammation. Complement analyses have been performed on these conditions in both prospective and retrospective studies and significant differences have been found between groups of patients, but in many diseases, it has not been possible to make predictions for individual patients because of the lack of sensitivity and specificity of many of the assays used. The basic indications for serological diagnostic complement analysis today may be divided into three major categories: (a acquired and inherited complement deficiencies; (b disorders with complement activation; (c inherited and acquired C1INH deficiencies. Here, we summarize indications, techniques, and interpretations for basic complement analyses and present an algorithm, which we follow in our routine laboratory.

  3. Role of Complement in Autoimmune Hemolytic Anemia.

    Science.gov (United States)

    Berentsen, Sigbjørn

    2015-09-01

    The classification of autoimmune hemolytic anemias and the complement system are reviewed. In autoimmune hemolytic anemia of the warm antibody type, complement-mediated cell lysis is clinically relevant in a proportion of the patients but is hardly essential for hemolysis in most patients. Cold antibody-mediated autoimmune hemolytic anemias (primary cold agglutinin disease, secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria) are entirely complement-mediated disorders. In cold agglutinin disease, efficient therapies have been developed in order to target the pathogenic B-cell clone, but complement modulation remains promising in some clinical situations. No established therapy exists for secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria, and the possibility of therapeutic complement inhibition is interesting. Currently, complement modulation is not clinically documented in any autoimmune hemolytic anemia. The most relevant candidate drugs and possible target levels of action are discussed.

  4. Role of Complement in Autoimmune Hemolytic Anemia

    OpenAIRE

    Berentsen, Sigbjørn

    2015-01-01

    Summary The classification of autoimmune hemolytic anemias and the complement system are reviewed. In autoimmune hemolytic anemia of the warm antibody type, complement-mediated cell lysis is clinically relevant in a proportion of the patients but is hardly essential for hemolysis in most patients. Cold antibody-mediated autoimmune hemolytic anemias (primary cold agglutinin disease, secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria) are entirely complement-mediated disorder...

  5. Pasteurella pneumotropica Evades the Human Complement System by Acquisition of the Complement Regulators Factor H and C4BP

    Science.gov (United States)

    Sahagún-Ruiz, Alfredo; Granados Martinez, Adriana Patricia; Breda, Leandro Carvalho Dantas; Fraga, Tatiana Rodrigues; Castiblanco Valencia, Mónica Marcela; Barbosa, Angela Silva; Isaac, Lourdes

    2014-01-01

    Pasteurella pneumotropica is an opportunist Gram negative bacterium responsible for rodent pasteurellosis that affects upper respiratory, reproductive and digestive tracts of mammals. In animal care facilities the presence of P. pneumotropica causes severe to lethal infection in immunodeficient mice, being also a potential source for human contamination. Indeed, occupational exposure is one of the main causes of human infection by P. pneumotropica. The clinical presentation of the disease includes subcutaneous abscesses, respiratory tract colonization and systemic infections. Given the ability of P. pneumotropica to fully disseminate in the organism, it is quite relevant to study the role of the complement system to control the infection as well as the possible evasion mechanisms involved in bacterial survival. Here, we show for the first time that P. pneumotropica is able to survive the bactericidal activity of the human complement system. We observed that host regulatory complement C4BP and Factor H bind to the surface of P. pneumotropica, controlling the activation pathways regulating the formation and maintenance of C3-convertases. These results show that P. pneumotropica has evolved mechanisms to evade the human complement system that may increase the efficiency by which this pathogen is able to gain access to and colonize inner tissues where it may cause severe infections. PMID:25347183

  6. Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome.

    Science.gov (United States)

    Orth, Dorothea; Khan, Abdul Basit; Naim, Asma; Grif, Katharina; Brockmeyer, Jens; Karch, Helge; Joannidis, Michael; Clark, Simon J; Day, Anthony J; Fidanzi, Sonja; Stoiber, Heribert; Dierich, Manfred P; Zimmerhackl, Lothar B; Würzner, Reinhard

    2009-05-15

    Infections with enterohemorrhagic Escherichia coli (EHEC) are a major cause of hemolytic uremic syndrome (HUS). Shiga toxins (Stxs), especially Stx2, are believed to represent major virulence factors of EHEC, contributing to HUS pathogenesis. Beside EHEC-associated HUS, there are hereditary atypical forms of HUS, which are mostly caused by mutations of complement regulators. The aim of the present study was to investigate whether or not complement is also involved in the pathogenesis of EHEC-induced typical HUS, by being activated either directly or indirectly by involvement of its inhibitors. Purified Stx2 markedly activated complement via the alternative pathway and was found to bind to factor H (FH), however, only when it was active. No apparent cleavage or destruction of FH was visible, and cofactor activity in fluid phase was unaffected, but clearly delayed for surface-attached FH, where it is essential for host cell protection. Binding studies using FH constructs revealed that Stx2 binds to short consensus repeats (SCRs) 6-8 and SCRs18-20, but not to SCRs16-17, i.e., to regions involved in the surface recognition function of FH. In conclusion, complement, and in particular FH, not only plays an important role in atypical HUS, but most probably also in EHEC-induced HUS.

  7. Differences in complement activation between complement-resistant and complement-sensitive Moraxella (Branhamella) catarrhalis strains occur at the level of membrane attack complex formation.

    OpenAIRE

    Verduin, C.M.; Jansze, M.; Hol, C; Mollnes, T E; Verhoef, J; Van Dijk, H.

    1994-01-01

    The mechanism of resistance to human complement-mediated killing in Moraxella catarrhalis was studied by comparing different complement-sensitive and complement-resistant M. catarrhalis strains in a functional bystander hemolysis assay and an enzyme-linked immunosorbent assay (ELISA) for soluble terminal complement complexes. Complement-resistant stains appeared to activate complement to the same extent as, or even slightly better than, complement-sensitive strains. This indicates that comple...

  8. On distribution of complementizers in contemporary Serbian

    Directory of Open Access Journals (Sweden)

    Moskovljević Jasmina

    2004-01-01

    Full Text Available The paper investigates the principles governing the distribution of complementizers in contemporary Serbian. Evidence is presented that the distribution of da, što, kako, gde, da li, and numerous interrogative pronouns and adverbials which may function as complementizers is determined not only by matrix-verb subcategorization properties and semantic co-occurrence restrictions which hold between the predicate and its complement, but by the lexical an syntactic properties of the particular verb class (or subclass to which matrix predicate belongs as well. According to their ability to govern a particular complementizer, ten major verb subclasses are identified in contemporary Serbian, and their specific properties are signaled.

  9. Role of Complement in Multiorgan Failure

    Directory of Open Access Journals (Sweden)

    Daniel Rittirsch

    2012-01-01

    Full Text Available Multiorgan failure (MOF represents the leading cause of death in patients with sepsis and systemic inflammatory response syndrome (SIRS following severe trauma. The underlying immune response is highly complex and involves activation of the complement system as a crucial entity of innate immunity. Uncontrolled activation of the complement system during sepsis and SIRS with in excessive generation of complement activation products contributes to an ensuing dysfunction of various organ systems. In the present review, mechanisms of the inflammatory response in the development of MOF in sepsis and SIRS with particular focus on the complement system are discussed.

  10. Local inflammation induces complement crosstalk which amplifies the antimicrobial response.

    Directory of Open Access Journals (Sweden)

    Jing Zhang

    2009-01-01

    Full Text Available By eliciting inflammatory responses, the human immunosurveillance system notably combats invading pathogens, during which acute phase proteins (CRP and cytokines are elevated markedly. However, the Pseudomonas aeruginosa is a persistent opportunistic pathogen prevalent at the site of local inflammation, and its acquisition of multiple antibiotic-resistance factors poses grave challenges to patient healthcare management. Using blood samples from infected patients, we demonstrate that P. aeruginosa is effectively killed in the plasma under defined local infection-inflammation condition, where slight acidosis and reduced calcium levels (pH 6.5, 2 mM calcium typically prevail. We showed that this powerful antimicrobial activity is provoked by crosstalk between two plasma proteins; CRPratioL-ficolin interaction led to communication between the complement classical and lectin pathways from which two amplification events emerged. Assays for C4 deposition, phagocytosis, and protein competition consistently proved the functional significance of the amplification pathways in boosting complement-mediated antimicrobial activity. The infection-inflammation condition induced a 100-fold increase in CRPratioL-ficolin interaction in a pH- and calcium-sensitive manner. We conclude that the infection-induced local inflammatory conditions trigger a strong interaction between CRPratioL-ficolin, eliciting complement-amplification pathways which are autonomous and which co-exist with and reinforce the classical and lectin pathways. Our findings provide new insights into the host immune response to P. aeruginosa infection under pathological conditions and the potential development of new therapeutic strategies against bacterial infection.

  11. The complement cascade as a mediator of tissue growth and regeneration.

    Science.gov (United States)

    Rutkowski, Martin J; Sughrue, Michael E; Kane, Ari J; Ahn, Brian J; Fang, Shanna; Parsa, Andrew T

    2010-11-01

    Recent evidence has demonstrated that the complement cascade is involved in a variety of physiologic and pathophysiologic processes in addition to its role as an immune effector. Research in a variety of organ systems has shown that complement proteins are direct participants in maintenance of cellular turnover, healing, proliferation and regeneration. As a physiologic housekeeper, complement proteins maintain tissue integrity in the absence of inflammation by disposing of cellular debris and waste, a process critical to the prevention of autoimmune disease. Developmentally, complement proteins influence pathways including hematopoietic stem cell engraftment, bone growth, and angiogenesis. They also provide a potent stimulus for cellular proliferation including regeneration of the limb and eye in animal models, and liver proliferation following injury. Here, we describe the complement cascade as a mediator of tissue growth and regeneration.

  12. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited.

    Science.gov (United States)

    Anderson, Don H; Radeke, Monte J; Gallo, Natasha B; Chapin, Ethan A; Johnson, Patrick T; Curletti, Christy R; Hancox, Lisa S; Hu, Jane; Ebright, Jessica N; Malek, Goldis; Hauser, Michael A; Rickman, Catherine Bowes; Bok, Dean; Hageman, Gregory S; Johnson, Lincoln V

    2010-03-01

    During the past ten years, dramatic advances have been made in unraveling the biological bases of age-related macular degeneration (AMD), the most common cause of irreversible blindness in western populations. In that timeframe, two distinct lines of evidence emerged which implicated chronic local inflammation and activation of the complement cascade in AMD pathogenesis. First, a number of complement system proteins, complement activators, and complement regulatory proteins were identified as molecular constituents of drusen, the hallmark extracellular deposits associated with early AMD. Subsequently, genetic studies revealed highly significant statistical associations between AMD and variants of several complement pathway-associated genes including: Complement factor H (CFH), complement factor H-related 1 and 3 (CFHR1 and CFHR3), complement factor B (CFB), complement component 2 (C2), and complement component 3 (C3). In this article, we revisit our original hypothesis that chronic local inflammatory and immune-mediated events at the level of Bruch's membrane play critical roles in drusen biogenesis and, by extension, in the pathobiology of AMD. Secondly, we report the results of a new screening for additional AMD-associated polymorphisms in a battery of 63 complement-related genes. Third, we identify and characterize the local complement system in the RPE-choroid complex - thus adding a new dimension of biological complexity to the role of the complement system in ocular aging and AMD. Finally, we evaluate the most salient, recent evidence that bears directly on the role of complement in AMD pathogenesis and progression. Collectively, these recent findings strongly re-affirm the importance of the complement system in AMD. They lay the groundwork for further studies that may lead to the identification of a transcriptional disease signature of AMD, and hasten the development of new therapeutic approaches that will restore the complement-modulating activity that

  13. New insights of an old defense system: structure, function, and clinical relevance of the complement system.

    Science.gov (United States)

    Ehrnthaller, Christian; Ignatius, Anita; Gebhard, Florian; Huber-Lang, Markus

    2011-01-01

    The complement system was discovered a century ago as a potent defense cascade of innate immunity. After its first description, continuous experimental and clinical research was performed, and three canonical pathways of activation were established. Upon activation by traumatic or surgical tissue damage, complement reveals beneficial functions of pathogen and danger defense by sensing and clearing injured cells. However, the latest research efforts have provided a more distinct insight into the complement system and its clinical subsequences. Complement has been shown to play a significant role in the pathogenesis of various inflammatory processes such as sepsis, multiorgan dysfunction, ischemia/reperfusion, cardiovascular diseases and many others. The three well-known activation pathways of the complement system have been challenged by newer findings that demonstrate direct production of central complement effectors (for example, C5a) by serine proteases of the coagulation cascade. In particular, thrombin is capable of producing C5a, which not only plays a decisive role on pathogens and infected/damaged tissues, but also acts systemically. In the case of uncontrolled complement activation, "friendly fire" is generated, resulting in the destruction of healthy host tissue. Therefore, the traditional research that focuses on a mainly positive-acting cascade has now shifted to the negative effects and how tissue damage originated by the activation of the complement can be contained. In a translational approach including structure-function relations of this ancient defense system, this review provides new insights of complement-mediated clinical relevant diseases and the development of complement modulation strategies and current research aspects.

  14. Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease.

    Science.gov (United States)

    Pandey, Manoj K; Burrow, Thomas A; Rani, Reena; Martin, Lisa J; Witte, David; Setchell, Kenneth D; Mckay, Mary A; Magnusen, Albert F; Zhang, Wujuan; Liou, Benjamin; Köhl, Jörg; Grabowski, Gregory A

    2017-03-02

    Gaucher disease is caused by mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA1 mutations drive extensive accumulation of glucosylceramide (GC) in multiple innate and adaptive immune cells in the spleen, liver, lung and bone marrow, often leading to chronic inflammation. The mechanisms that connect excess GC to tissue inflammation remain unknown. Here we show that activation of complement C5a and C5a receptor 1 (C5aR1) controls GC accumulation and the inflammatory response in experimental and clinical Gaucher disease. Marked local and systemic complement activation occurred in GCase-deficient mice or after pharmacological inhibition of GCase and was associated with GC storage, tissue inflammation and proinflammatory cytokine production. Whereas all GCase-inhibited mice died within 4-5 weeks, mice deficient in both GCase and C5aR1, and wild-type mice in which GCase and C5aR were pharmacologically inhibited, were protected from these adverse effects and consequently survived. In mice and humans, GCase deficiency was associated with strong formation of complement-activating GC-specific IgG autoantibodies, leading to complement activation and C5a generation. Subsequent C5aR1 activation controlled UDP-glucose ceramide glucosyltransferase production, thereby tipping the balance between GC formation and degradation. Thus, extensive GC storage induces complement-activating IgG autoantibodies that drive a pathway of C5a generation and C5aR1 activation that fuels a cycle of cellular GC accumulation, innate and adaptive immune cell recruitment and activation in Gaucher disease. As enzyme replacement and substrate reduction therapies are expensive and still associated with inflammation, increased risk of cancer and Parkinson disease, targeting C5aR1 may serve as a treatment option for patients with Gaucher disease and, possibly, other lysosomal storage diseases.

  15. Disulfiram deregulates HIF-α subunits and blunts tumor adaptation to hypoxia in hepatoma cells

    Science.gov (United States)

    Park, Hye-joon; Kim, Min-sung; Cho, Kumsun; Yun, Jang-hyuk; Choi, Yong-joon; Cho, Chung-hyun

    2013-01-01

    Aim: Disulfiram is an aldehyde dehydrogenase inhibitor that was used to treat alcoholism and showed anticancer activity, but its anticancer mechanism remains unclear. The aim of this study was to investigate the effects of disulfiram on the hypoxia-inducible factor (HIF)-driven tumor adaptation to hypoxia in vitro. Methods: Hep3B, Huh7 and HepG2 hepatoma cells were incubated under normoxic (20% O2) or hypoxic (1% O2) conditions for 16 h. The expression and activity of HIF-1α and HIF-2α proteins were evaluated using immunoblotting and luciferase reporter assay, respectively. Semi-quantitative RT-PCR was used to analyze HIF-mediated gene expression. Endothelial tubule formation assay was used to evaluate the anti-angiogenic effect. Results: Hypoxia caused marked expression of HIF-1α and HIF-1α in the 3 hepatoma cell lines, dramatically increased HIF activity and induced the expression of HIF downstream genes (EPO, CA9, VEGF-A and PDK1) in Hep3B cells. HIF-2α expression was positively correlated with the induction of hypoxic genes (CA9, VEGF-A and PDK1). Moreover, hypoxia markedly increased VEGF production and angiogenic potential of Hep3B cells. Disulfiram (0.3 to 2 μmol/L) inhibited hypoxia-induced gene expression and HIF activity in a dose-dependent manner. Disulfiram more effectively suppressed the viability of Hep3B cells under hypoxia, but it did not affect the cell cycle. Overexpression of HIF-2α in Hep3B cells reversed the inhibitory effects of disulfiram on hypoxia-induced gene expression and cell survival under hypoxia. Conclusion: Disulfiram deregulates the HIF-mediated hypoxic signaling pathway in hepatoma cells, which may contribute to its anticancer effect. Thus, disulfiram could be used to treat solid tumors that grow in a HIF-dependent manner. PMID:23852087

  16. Nitric oxide-releasing prodrug triggers cancer cell death through deregulation of cellular redox balance

    Directory of Open Access Journals (Sweden)

    Anna E. Maciag

    2013-01-01

    Full Text Available JS-K is a nitric oxide (NO-releasing prodrug of the O2-arylated diazeniumdiolate family that has demonstrated pronounced cytotoxicity and antitumor properties in a variety of cancer models both in vitro and in vivo. The current study of the metabolic actions of JS-K was undertaken to investigate mechanisms of its cytotoxicity. Consistent with model chemical reactions, the activating step in the metabolism of JS-K in the cell is the dearylation of the diazeniumdiolate by glutathione (GSH via a nucleophilic aromatic substitution reaction. The resulting product (CEP/NO anion spontaneously hydrolyzes, releasing two equivalents of NO. The GSH/GSSG redox couple is considered to be the major redox buffer of the cell, helping maintain a reducing environment under basal conditions. We have quantified the effects of JS-K on cellular GSH content, and show that JS-K markedly depletes GSH, due to JS-K's rapid uptake and cascading release of NO and reactive nitrogen species. The depletion of GSH results in alterations in the redox potential of the cellular environment, initiating MAPK stress signaling pathways, and inducing apoptosis. Microarray analysis confirmed signaling gene changes at the transcriptional level and revealed alteration in the expression of several genes crucial for maintenance of cellular redox homeostasis, as well as cell proliferation and survival, including MYC. Pre-treating cells with the known GSH precursor and nucleophilic reducing agent N-acetylcysteine prevented the signaling events that lead to apoptosis. These data indicate that multiplicative depletion of the reduced glutathione pool and deregulation of intracellular redox balance are important initial steps in the mechanism of JS-K's cytotoxic action.

  17. Deregulated sex chromosome gene expression with male germ cell-specific loss of Dicer1.

    Science.gov (United States)

    Greenlee, Anne R; Shiao, Meng-Shin; Snyder, Elizabeth; Buaas, F William; Gu, Tongjun; Stearns, Timothy M; Sharma, Manju; Murchison, Elizabeth P; Puente, Gabriella C; Braun, Robert E

    2012-01-01

    MicroRNAs (miRNAs) are a class of endogenous, non-coding RNAs that mediate post-transcriptional gene silencing by inhibiting mRNA translation and promoting mRNA decay. DICER1, an RNase III endonuclease encoded by Dicer1, is required for processing short 21-22 nucleotide miRNAs from longer double-stranded RNA precursors. Here, we investigate the loss of Dicer1 in mouse postnatal male germ cells to determine how disruptions in the miRNA biogenesis pathway may contribute to infertility. Reduced levels of Dicer1 transcripts and DICER1 were confirmed in germ cell knock-out (GCKO) testes by postnatal day 18 (P18). Compared to wild-type (WT) at 8 weeks, GCKO males had no change in body weight; yet showed significant reductions in testis mass and sperm number. Histology and fertility tests confirmed spermatogenic failure in GCKO males. Array analyses at P18 showed that in comparison to WT testes, 75% of miRNA genes and 37% of protein coding genes were differentially expressed in GCKO testes. Among these, 96% of miRNA genes were significantly down-regulated, while 4% miRNA genes were overexpressed. Interestingly, we observed preferential overexpression of genes encoded on the sex chromosomes in GCKO testes, including more than 80% of previously identified targets of meiotic sex chromosome inactivation (MSCI). Compared to WT, GCKO mice showed higher percentages of germ cells at early meiotic stages (leptotene and zygotene) but lower percentages at later stages (pachytene, diplotene and metaphase I) providing evidence that deletion of Dicer1 leads to disruptions in meiotic progression. Therefore, deleting Dicer1 in early postnatal germ cells resulted in deregulation of transcripts encoded by genes on the sex chromosomes, impaired meiotic progression and led to spermatogenic failure and infertility.

  18. Deregulated sex chromosome gene expression with male germ cell-specific loss of Dicer1.

    Directory of Open Access Journals (Sweden)

    Anne R Greenlee

    Full Text Available MicroRNAs (miRNAs are a class of endogenous, non-coding RNAs that mediate post-transcriptional gene silencing by inhibiting mRNA translation and promoting mRNA decay. DICER1, an RNase III endonuclease encoded by Dicer1, is required for processing short 21-22 nucleotide miRNAs from longer double-stranded RNA precursors. Here, we investigate the loss of Dicer1 in mouse postnatal male germ cells to determine how disruptions in the miRNA biogenesis pathway may contribute to infertility. Reduced levels of Dicer1 transcripts and DICER1 were confirmed in germ cell knock-out (GCKO testes by postnatal day 18 (P18. Compared to wild-type (WT at 8 weeks, GCKO males had no change in body weight; yet showed significant reductions in testis mass and sperm number. Histology and fertility tests confirmed spermatogenic failure in GCKO males. Array analyses at P18 showed that in comparison to WT testes, 75% of miRNA genes and 37% of protein coding genes were differentially expressed in GCKO testes. Among these, 96% of miRNA genes were significantly down-regulated, while 4% miRNA genes were overexpressed. Interestingly, we observed preferential overexpression of genes encoded on the sex chromosomes in GCKO testes, including more than 80% of previously identified targets of meiotic sex chromosome inactivation (MSCI. Compared to WT, GCKO mice showed higher percentages of germ cells at early meiotic stages (leptotene and zygotene but lower percentages at later stages (pachytene, diplotene and metaphase I providing evidence that deletion of Dicer1 leads to disruptions in meiotic progression. Therefore, deleting Dicer1 in early postnatal germ cells resulted in deregulation of transcripts encoded by genes on the sex chromosomes, impaired meiotic progression and led to spermatogenic failure and infertility.

  19. Discriminating complement-mediated acute transfusion reaction for type O+ red blood cells transfused into a B+ recipient with the complement hemolysis using human erythrocytes (CHUHE) assay.

    Science.gov (United States)

    Cunnion, Kenji M; Hair, Pamela S; Krishna, Neel K; Whitley, Pamela H; Goldberg, Corinne L; Fadeyi, Emmanuel A; Maes, Lanne Y

    2016-07-01

    A patient with B+ sickle cell disease received 3 units of red blood cells (RBCs) from two O+ donors and developed fever and hypotension after the first unit, consistent with an acute transfusion reaction (ATR). Anti-B titers in plasma from each O+ donor were markedly elevated and nondiscriminatory. In order to evaluate the potential for the transfused units to produce complement-mediated hemolysis of B+ RBCs, hemolytic complement testing was performed. Plasma from each donor was diluted in veronal buffer and incubated with B+ RBCs, and free hemoglobin was measured by spectrophotometer in the complement hemolysis using human erythrocytes (CHUHE) assay. Peptide inhibitor of complement C1 (PIC1) was used to confirm antibody-initiated complement pathway activation. A 96-fold difference (p = 0.014) in hemolysis was measured between plasma samples from the two O+ donors using the CHUHE assay. The extremely high degree of hemolysis produced by the one plasma was inhibited by PIC1 in a dose-dependent manner. These results indicate that hemolytic complement testing with the CHUHE assay can be used to assess the risk of antibody-initiated, complement-mediated hemolysis from a transfusion beyond what can be achieved with antibody titers alone. © 2016 AABB.

  20. Complement factor H deficiency and endocapillary glomerulonephritis due to paternal isodisomy and a novel factor H mutation

    DEFF Research Database (Denmark)

    Schejbel, L; Schmidt, I M; Kirchhoff, Eva Maria;

    2011-01-01

    Complement factor H (CFH) is a regulator of the alternative complement activation pathway. Mutations in the CFH gene are associated with atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II and C3 glomerulonephritis. Here, we report a 6-month-old CFH-deficient child...

  1. Peripheral challenge with a viral mimic upregulates expression of the complement genes in the hippocampus.

    Science.gov (United States)

    Michalovicz, Lindsay T; Lally, Brent; Konat, Gregory W

    2015-08-15

    Peripheral challenge with a viral mimetic, polyinosinic-polycytidylic acid (PIC) induces hippocampal hyperexcitability in mice. Here, we characterized this hippocampal response through a whole genome transcriptome analysis. Intraperitoneal injection of PIC resulted in temporal dysregulation of 625 genes in the hippocampus, indicating an extensive genetic reprogramming. The bioinformatics analysis of these genes revealed the complement pathway to be the most significantly activated. The gene encoding complement factor B (CfB) exhibited the highest response, and its upregulation was commensurate with the development of hyperexcitability. Collectively, these results suggest that the induction of hippocampal hyperexcitability may be mediated by the alternative complement cascades.

  2. Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide.

    Science.gov (United States)

    Bradt, B M; Kolb, W P; Cooper, N R

    1998-08-03

    Large numbers of neuritic plaques (NP), largely composed of a fibrillar insoluble form of the beta-amyloid peptide (Abeta), are found in the hippocampus and neocortex of Alzheimer's disease (AD) patients in association with damaged neuronal processes, increased numbers of activated astrocytes and microglia, and several proteins including the components of the proinflammatory complement system. These studies address the hypothesis that the activated complement system mediates the cellular changes that surround fibrillar Abeta deposits in NP. We report that Abeta peptides directly and independently activate the alternative complement pathway as well as the classical complement pathway; trigger the formation of covalent, ester-linked complexes of Abeta with activation products of the third complement component (C3); generate the cytokine-like C5a complement-activation fragment; and mediate formation of the proinflammatory C5b-9 membrane attack complex, in functionally active form able to insert into and permeabilize the membrane of neuronal precursor cells. These findings provide inflammation-based mechanisms to account for the presence of complement components in NP in association with damaged neurons and increased numbers of activated glial cells, and they have potential implications for the therapy of AD.

  3. Therapeutic targeting of the complement system in age-related macular degeneration: a review.

    Science.gov (United States)

    Troutbeck, Robyn; Al-Qureshi, Salmaan; Guymer, Robyn H

    2012-01-01

    The last decade has produced pivotal change in our understanding of the molecular mechanisms underlying age-related macular degeneration (AMD), a leading cause of global blindness. In this time, the complement system has featured as a unifying theme for several elements of new evidence: initially, the discovery of complement proteins within drusen and subsequently, the association between AMD and mutations in various complement pathway genes, most notably complement factor H. Increasingly, a wealth of data are pointing towards a role for chronic local inflammation and complement activation in the patho-aetiology of AMD. These findings have paved the way for the exploration of a new paradigm of therapy in AMD management; targeting of specific molecular constituents in the complement pathway thus producing dampening or inhibition of the inflammatory response. Such an approach has the potential to intervene earlier in the disease process and ideally before vision is compromised. In this review we discuss the role of the complement system in AMD, novel therapies in preclinical evaluation and clinical trial, and whether these have a part to play in reducing the burden of disease.

  4. Noun complement clauses as referential modifiers

    Directory of Open Access Journals (Sweden)

    Carlos de Cuba

    2017-01-01

    Full Text Available A number of recent analyses propose that so-called noun complement clauses should be analyzed as a type of relative clause. In this paper, I present a number of complications for any analysis that equates noun complement clauses to relative clauses, and conclude that this type of analysis is on the wrong track. I present cross-linguistic evidence showing that the syntactic behavior of noun complement clauses does not pattern with relative clauses. Patterns of complementizer choice and complementizer drop as well as patterns involving main clause phenomena and extraction differ in the two constructions, which I argue is unexpected under a relative clause analysis that involves operator movement. Instead I present an alternative analysis in which I propose that the referentiality of a noun complement clause is linked to its syntactic behavior. Following recent work, I claim that referential clauses have a syntactically truncated left-periphery, and this truncation can account for the lack of main clause phenomena in noun complement clauses. I argue that the truncation analysis is also able to accommodate complementizer data patterns more easily than relative clause analyses that appeal to operator movement.

  5. Hyperbolic structures on a toric arrangement complement

    NARCIS (Netherlands)

    Shen, Dali

    2015-01-01

    This thesis studies the geometric structures on toric arrangement complements. Inspired by the special hypergeometric functions associated with a root system, we consider a family of connections on a total space which is the product of the complement of a toric arrangement (=finite union of hypertor

  6. The complement system in systemic autoimmune disease

    NARCIS (Netherlands)

    Chen, Min; Daha, Mohamed R.; Kallenberg, Cees G. M.

    2010-01-01

    Complement is part of the innate immune system. Its major function is recognition and elimination of pathogens via direct killing and/or stimulation of phagocytosis. Activation of the complement system is, however, also involved in the pathogenesis of the systemic autoimmune diseases. Activation via

  7. Current evidence for the role of complement in the pathogenesis of Shiga toxin haemolytic uraemic syndrome.

    Science.gov (United States)

    Keir, Lindsay S; Saleem, Moin A

    2014-10-01

    Shiga toxin-associated haemolytic uraemic syndrome (Stx HUS) is the leading cause of paediatric acute kidney injury. This toxin-mediated disease carries a significant morbidity and mortality but has no direct treatments. Rare familial atypical HUS (aHUS) is now understood to result from over-activation of the alternative complement pathway causing glomerular endothelial damage. By understanding the pathogenic mechanisms of this disease, the monoclonal antibody eculizumab, which blocks the final common pathway of complement, is now being used to treat aHUS. For this reason, clinicians and scientists are studying the role of the alternative complement pathway in Stx HUS with the aim of targeting treatment in a similar way. There is some evidence suggesting that complement plays a role in the pathogenesis of Stx HUS, but other mechanisms may also be important. Clinically, modulating the complement system using plasma exchange provides no proven benefit in Stx HUS, and the use of eculizumab has provided conflicting results. Understanding the local effect of Stx on the glomerulus, in particular regulation of the complement and coagulation systems, may lead to advances in defining the precise pathogenesis of this disease. Then, targeted treatment strategies could be devised and clinical trials undertaken.

  8. Human pentraxin 3 binds to the complement regulator c4b-binding protein.

    Directory of Open Access Journals (Sweden)

    Anne Braunschweig

    Full Text Available The long pentraxin 3 (PTX3 is a soluble recognition molecule with multiple functions including innate immune defense against certain microbes and the clearance of apoptotic cells. PTX3 interacts with recognition molecules of the classical and lectin complement pathways and thus initiates complement activation. In addition, binding of PTX3 to the alternative complement pathway regulator factor H was shown. Here, we show that PTX3 binds to the classical and lectin pathway regulator C4b-binding protein (C4BP. A PTX3-binding site was identified within short consensus repeats 1-3 of the C4BP α-chain. PTX3 did not interfere with the cofactor activity of C4BP in the fluid phase and C4BP maintained its complement regulatory activity when bound to PTX3 on surfaces. While C4BP and factor H did not compete for PTX3 binding, the interaction of C4BP with PTX3 was inhibited by C1q and by L-ficolin. PTX3 bound to human fibroblast- and endothelial cell-derived extracellular matrices and recruited functionally active C4BP to these surfaces. Whereas PTX3 enhanced the activation of the classical/lectin pathway and caused enhanced C3 deposition on extracellular matrix, deposition of terminal pathway components and the generation of the inflammatory mediator C5a were not increased. Furthermore, PTX3 enhanced the binding of C4BP to late apoptotic cells, which resulted in an increased rate of inactivation of cell surface bound C4b and a reduction in the deposition of C5b-9. Thus, in addition to complement activators, PTX3 interacts with complement inhibitors including C4BP. This balanced interaction on extracellular matrix and on apoptotic cells may prevent excessive local complement activation that would otherwise lead to inflammation and host tissue damage.

  9. Crosstalk between Complement and Toll-like Receptor Activation in Relation to Donor Brain Death and Renal Ischemia-Reperfusion Injury

    NARCIS (Netherlands)

    Damman, Jeffrey; Daha, Mohamed R.; van Son, Willem J.; Leuvenink, Henri G.; Ploeg, Rutger J.; Seelen, Marc A.

    2011-01-01

    Two central pathways of innate immunity, complement and Toll-like receptors (TLRs), play an important role in the pathogenesis of renal injury inherent to kidney transplantation. Recent findings indicate close crosstalk between complement and TLR signaling pathways. It is suggested that mitogen acti

  10. Crosstalk between Complement and Toll-like Receptor Activation in Relation to Donor Brain Death and Renal Ischemia-Reperfusion Injury

    NARCIS (Netherlands)

    Damman, Jeffrey; Daha, Mohamed R.; van Son, Willem J.; Leuvenink, Henri G.; Ploeg, Rutger J.; Seelen, Marc A.

    2011-01-01

    Two central pathways of innate immunity, complement and Toll-like receptors (TLRs), play an important role in the pathogenesis of renal injury inherent to kidney transplantation. Recent findings indicate close crosstalk between complement and TLR signaling pathways. It is suggested that mitogen acti

  11. Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q.

    Science.gov (United States)

    Honda-Ogawa, Mariko; Sumitomo, Tomoko; Mori, Yasushi; Hamd, Dalia Talat; Ogawa, Taiji; Yamaguchi, Masaya; Nakata, Masanobu; Kawabata, Shigetada

    2017-03-10

    Streptococcus pyogenes secretes various virulence factors for evasion from complement-mediated bacteriolysis. However, full understanding of the molecules possessed by this organism that interact with complement C1q, an initiator of the classical complement pathway, remains elusive. In this study, we identified an endopeptidase of S. pyogenes, PepO, as an interacting molecule, and investigated its effects on complement immunity and pathogenesis. Enzyme-linked immunosorbent assay and surface plasmon resonance analysis findings revealed that S. pyogenes recombinant PepO bound to human C1q in a concentration-dependent manner under physiological conditions. Sites of inflammation are known to have decreased pH levels, thus the effects of PepO on bacterial evasion from complement immunity was analyzed in a low pH condition. Notably, under low pH conditions, PepO exhibited a higher affinity for C1q as compared with IgG, and PepO inhibited the binding of IgG to C1q. In addition, pepO deletion rendered S. pyogenes more susceptible to the bacteriocidal activity of human serum. Also, observations of the morphological features of the pepO mutant strain (ΔpepO) showed damaged irregular surfaces as compared with the wild-type strain (WT). WT-infected tissues exhibited greater severity and lower complement activity as compared with those infected by ΔpepO in a mouse skin infection model. Furthermore, WT infection resulted in a larger accumulation of C1q than that with ΔpepO. Our results suggest that interaction of S. pyogenes PepO with C1q interferes with the complement pathway, which enables S. pyogenes to evade complement-mediated bacteriolysis under acidic conditions, such as seen in inflammatory sites. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Complement activation by Pseudomonas aeruginosa biofilms

    DEFF Research Database (Denmark)

    Jensen, E T; Kharazmi, A; Garred, P

    1993-01-01

    In chronic infections, such as the bronchopulmonary Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients, bacteria persist despite an intact host immune defense and frequent antibiotic treatment. An important reason for the persistence of the bacteria is their capacity for the biofilm...... mode of growth. In this study we investigated the role of biofilms in activation of complement, a major contributor to the inflammatory process. Complement activation by P. aeruginosa was examined in a complement consumption assay, production of C3 and factor B conversion products assessed by crossed...... immuno-electrophoresis, C5a generation tested by a PMN chemotactic assay, and terminal complement complex formation measured by ELISA. Two of the four assays showed that P. aeruginosa grown in biofilm activated complement less than planktonic bacteria, and all assays showed that activation by intact...

  13. Complement system part II: role in immunity

    Directory of Open Access Journals (Sweden)

    Nicolas S. Merle

    2015-05-01

    Full Text Available The complement system has been considered for a long time as a simple lytic system, aimed to kill bacteria infecting the host organism. Nowadays this vision has changed and it is well accepted that complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation and in the defense against pathogens. This review discusses recent advances in the understanding of the role of complement in physiology and pathology. It starts with a description of complement contribution to the normal physiology (homeostasis of a healthy organism, including the silent clearance of apoptotic cells and maintenance of cell survival. In pathology, complement can be a friend or a foe. It acts as a friend in the defense against pathogens, by inducing a direct killing by C5b-9 membrane attack complex by triggering inflammatory responses with the anaphylatoxins C3a and C5a and helps the mounting of an adaptive immune response, involving antigen presenting cells, T- and B- lymphocytes. But it can be also an enemy, when pathogens hijack complement regulators to protect themselves from the immune system. Also examples will be discussed, where inadequate complement activation becomes a disease cause, including atypical hemolytic uremic syndrome (aHUS, C3 glomerulopathies (C3G and systemic lupus erythematosus (SLE. Age related macular degeneration (AMD and cancer will be described as examples showing that complement contributes to a large variety of diseases, far exceeding the classical examples of diseases associated with complement deficiencies. Finally, we discuss complement as a therapeutic target.

  14. Complement System Part II: Role in Immunity

    Science.gov (United States)

    Merle, Nicolas S.; Noe, Remi; Halbwachs-Mecarelli, Lise; Fremeaux-Bacchi, Veronique; Roumenina, Lubka T.

    2015-01-01

    The complement system has been considered for a long time as a simple lytic cascade, aimed to kill bacteria infecting the host organism. Nowadays, this vision has changed and it is well accepted that complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation, and in the defense against pathogens. This review discusses recent advances in the understanding of the role of complement in physiology and pathology. It starts with a description of complement contribution to the normal physiology (homeostasis) of a healthy organism, including the silent clearance of apoptotic cells and maintenance of cell survival. In pathology, complement can be a friend or a foe. It acts as a friend in the defense against pathogens, by inducing opsonization and a direct killing by C5b–9 membrane attack complex and by triggering inflammatory responses with the anaphylatoxins C3a and C5a. Opsonization plays also a major role in the mounting of an adaptive immune response, involving antigen presenting cells, T-, and B-lymphocytes. Nevertheless, it can be also an enemy, when pathogens hijack complement regulators to protect themselves from the immune system. Inadequate complement activation becomes a disease cause, as in atypical hemolytic uremic syndrome, C3 glomerulopathies, and systemic lupus erythematosus. Age-related macular degeneration and cancer will be described as examples showing that complement contributes to a large variety of conditions, far exceeding the classical examples of diseases associated with complement deficiencies. Finally, we discuss complement as a therapeutic target. PMID:26074922

  15. Integrative identification of deregulated miRNA/TF-mediated gene regulatory loops and networks in prostate cancer.

    Science.gov (United States)

    Afshar, Ali Sobhi; Xu, Joseph; Goutsias, John

    2014-01-01

    MicroRNAs (miRNAs) have attracted a great deal of attention in biology and medicine. It has been hypothesized that miRNAs interact with transcription factors (TFs) in a coordinated fashion to play key roles in regulating signaling and transcriptional pathways and in achieving robust gene regulation. Here, we propose a novel integrative computational method to infer certain types of deregulated miRNA-mediated regulatory circuits at the transcriptional, post-transcriptional and signaling levels. To reliably predict miRNA-target interactions from mRNA/miRNA expression data, our method collectively utilizes sequence-based miRNA-target predictions obtained from several algorithms, known information about mRNA and miRNA targets of TFs available in existing databases, certain molecular structures identified to be statistically over-represented in gene regulatory networks, available molecular subtyping information, and state-of-the-art statistical techniques to appropriately constrain the underlying analysis. In this way, the method exploits almost every aspect of extractable information in the expression data. We apply our procedure on mRNA/miRNA expression data from prostate tumor and normal samples and detect numerous known and novel miRNA-mediated deregulated loops and networks in prostate cancer. We also demonstrate instances of the results in a number of distinct biological settings, which are known to play crucial roles in prostate and other types of cancer. Our findings show that the proposed computational method can be used to effectively achieve notable insights into the poorly understood molecular mechanisms of miRNA-mediated interactions and dissect their functional roles in cancer in an effort to pave the way for miRNA-based therapeutics in clinical settings.

  16. Complement modulation of T cell immune responses during homeostasis and disease.

    Science.gov (United States)

    Clarke, Elizabeth V; Tenner, Andrea J

    2014-11-01

    The complement system is an ancient and critical effector mechanism of the innate immune system as it senses, kills, and clears infectious and/or dangerous particles and alerts the immune system to the presence of the infection and/or danger. Interestingly, an increasing number of reports have demonstrated a clear role for complement in the adaptive immune system as well. Of note, a number of recent studies have identified previously unknown roles for complement proteins, receptors, and regulators in T cell function. Here, we will review recent data demonstrating the influence of complement proteins C1q, C3b/iC3b, C3a (and C3aR), and C5a (and C5aR) and complement regulators DAF (CD55) and CD46 (MCP) on T cell function during homeostasis and disease. Although new concepts are beginning to emerge in the field of complement regulation of T cell function, future experiments should focus on whether complement is interacting directly with the T cell or is having an indirect effect on T cell function via APCs, the cytokine milieu, or downstream complement activation products. Importantly, the identification of the pivotal molecular pathways in the human systems will be beneficial in the translation of concepts derived from model systems to therapeutic targeting for treatment of human disorders.

  17. Interactions of the complement system with molecules of extracellular matrix: relevance for joint diseases.

    Science.gov (United States)

    Happonen, Kaisa E; Heinegård, Dick; Saxne, Tore; Blom, Anna M

    2012-11-01

    Rheumatoid arthritis (RA) is a highly disabling disease affecting all structures of the joint. Understanding the pathology behind the development of RA is essential for developing targeted therapeutic strategies as well as for developing novel markers to predict disease onset. Several molecules normally hidden within the cartilage tissue are exposed to complement components in the synovial fluid upon cartilage breakdown. Some of these have been shown to activate complement and toll-like receptors, which may enhance an already existing inflammatory response, thereby worsening the course of disease. Other cartilage-resident molecules have in contrast shown to possess complement-inhibitory properties. Knowledge about mechanisms behind pathological complement activation in the joints will hopefully lead to methods which allow us to distinguish patients with pathological complement activation from those where other inflammatory pathways are predominant. This will help to elucidate which patients will benefit from complement inhibitory therapies, which are thought to aid a specific subset of patients or patients at a certain stage of disease. Future challenges are to target the complement inhibition specifically to the joints to minimize systemic complement blockade.

  18. Complement activation by cholesterol crystals triggers a subsequent cytokine response

    DEFF Research Database (Denmark)

    Niyonzima, Nathalie; Halvorsen, Bente; Sporsheim, Bjørnar

    2017-01-01

    may under certain circumstances drive processes leading to adverse inflammation. One example is cholesterol crystals (CC) that accumulate in the vessel wall during early phases of atherogenesis and represent an important endogenous danger signal promoting inflammation. CC is recognized by the lectin...... of inflammation processes before downstream release of cytokines including IL-1β. Another therapeutic candidate can be broad-acting 2-hydroxypropyl-β-cyclodextrin, a compound that targets several mechanisms such as cholesterol efflux, complement gene expression, and the NLRP3 pathway. In summary, emerging...

  19. Does deregulation in community pharmacy impact accessibility of medicines, quality of pharmacy services and costs? Evidence from nine European countries.

    Science.gov (United States)

    Vogler, Sabine; Habimana, Katharina; Arts, Danielle

    2014-09-01

    To analyse the impact of deregulation in community pharmacy on accessibility of medicines, quality of pharmacy services and costs. We analysed and compared community pharmacy systems in five rather deregulated countries (England, Ireland, the Netherlands, Norway, Sweden) and four rather regulated countries (Austria, Denmark, Finland, Spain). Data were collected by literature review, a questionnaire survey and interviews. Following a deregulation, several new pharmacies and dispensaries of Over-the-Counter (OTC) medicines tended to be established, predominantly in urban areas. Unless prevented by regulation, specific stakeholders, e.g. wholesalers, were seen to gain market dominance which limited envisaged competition. There were indications for an increased workload for pharmacists in some deregulated countries. Economic pressure to increase the pharmacy turnover through the sale of OTC medicines and non-pharmaceuticals was observed in deregulated and regulated countries. Prices of OTC medicines were not found to decrease after a deregulation in pharmacy. Access to pharmacies usually increases after a deregulation but this is likely to favour urban populations with already good accessibility. Policy-makers are recommended to take action to ensure equitable accessibility and sustainable competition in a more deregulated environment. No association between pharmaceutical expenditure and the extent of regulation/deregulation appears to exist. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. Viral mimicry of the complement system

    Indian Academy of Sciences (India)

    John Bernet; Jayati Mullick; Akhilesh K Singh; Arvind Sahu

    2003-04-01

    The complement system is a potent innate immune mechanism consisting of cascades of proteins which are designed to fight against and annul intrusion of all the foreign pathogens. Although viruses are smaller in size and have relatively simple structure, they are not immune to complement attack. Thus, activation of the complement system can lead to neutralization of cell-free viruses, phagocytosis of C3b-coated viral particles, lysis of virus-infected cells, and generation of inflammatory and specific immune responses. However, to combat host responses and succeed as pathogens, viruses not only have developed/adopted mechanisms to control complement, but also have turned these interactions to their own advantage. Important examples include poxviruses, herpesviruses, retroviruses, paramyxoviruses and picornaviruses. In this review, we provide information on the various complement evasion strategies that viruses have developed to thwart the complement attack of the host. A special emphasis is given on the interactions between the viral proteins that are involved in molecular mimicry and the complement system.

  1. Modulatory Role of Surface Coating of Superparamagnetic Iron Oxide Nanoworms in Complement Opsonization and Leukocyte Uptake

    DEFF Research Database (Denmark)

    Inturi, Swetha; Wang, Guankui; Chen, Fangfang

    2015-01-01

    Notwithstanding rapid advances of nanotechnology in diagnostic imaging and drug delivery, the engineered nanocarriers still exhibit substantial lack of hemocompatibility. Thus, when injected systemically, nanoparticles are avidly recognized by blood leukocytes and platelets, but the mechanisms of...... alternative pathway and by nanoparticle surface coating. These results provide important insights into the mechanisms of hemocompatibility of nanomedicines....... demonstrated that neutrophils, monocytes, lymphocytes and eosinophils took up SPIO NWs, and the uptake was prevented by EDTA (a general complement inhibitor) and by antiproperdin antibody (an inhibitor of the alternative pathway of the complement system). Cross-linking and hydrogelation of SPIO NWs surface...

  2. Learning without experience: Understanding the strategic implications of deregulation and competition in the electricity industry

    Energy Technology Data Exchange (ETDEWEB)

    Lomi, A. [School of Economics, University of Bologna, Bologna (Italy); Larsen, E.R. [Dept. of Managements Systems and Information, City University Business School, London (United Kingdom)

    1998-11-01

    As deregulation of the electricity industry continues to gain momentum around the world, electricity companies face unprecedented challenges. Competitive complexity and intensity will increase substantially as deregulated companies find themselves competing in new industries, with new rules, against unfamiliar competitors - and without any history to learn from. We describe the different kinds of strategic issues that newly deregulated utility companies are facing, and the risks that strategic issues implicate. We identify a number of problems induced by experiential learning under conditions of competence-destroying change, and we illustrate ways in which companies can activate history-independent learning processes. We suggest that Micro worlds - a new generation of computer-based learning environments made possible by conceptual and technological progress in the fields of system dynamics and systems thinking - are particularly appropriate tools to accelerate and enhance organizational and managerial learning under conditions of increased competitive complexity. (au)

  3. Evolutionary Programming Based Optimal Placement of UPFC Device in Deregulated Electricity Market

    Directory of Open Access Journals (Sweden)

    Mr. K. Balamurugan

    2014-01-01

    Full Text Available In deregulated power industry, the real time pricing of real power has an important issue to create fair open access and great impact of efficient and economics operation of deregulated electricity market. FACTS devices can be used to control the power flows. Therefore the optimal allocation of FACTS device can be used to achieve the optimal power flow without any constraints violation and thus to increase the utilization of the lowest cost generation in power system network. This paper proposes a new method of optimal placement of Unified power flow controller (FACTS devices in Deregulated Electricity Market using Evolutionary Programming. Using proposed method, the allocation of UPFC devices and ratings are optimized. The main objective function is to minimizing the overall system cost, which includes the investment cost of UPFC device and bid offers of the market participants. The effectiveness of the proposed method is demonstrated on IEEE 14-bus system.

  4. Proteomic Analysis Reveals the Deregulation of Inflammation-Related Proteins in Acupuncture-Treated Rats with Asthma Onset

    Directory of Open Access Journals (Sweden)

    Yu-Dong Xu

    2012-01-01

    Full Text Available Although the beneficial effects of acupuncture in asthma treatment have been well documented, little is known regarding the biological basis of this treatment. Changes in the lung proteome of acupuncture-treated rats with asthma onset were comparatively analyzed using a two-dimensional gel electrophoresis (2DE and mass-spectrometry- (MS- based proteomic approach. Acupuncture on specific acupuncture points appeared to improve respiratory function and reduce the total number of leukocytes and eosinophils in bronchoalveolar lavage fluid in OVA-induced asthma onset. Image analysis of 2DE gels revealed 32 differentially expressed acupuncture-specific protein spots in asthma onset; 30 of which were successfully identified as 28 unique proteins using LC-MS/MS. Bioinformatic analyses indicated that these altered proteins are most likely involved in inflammation-related biological functions, and the functional associations of these proteins result in an inflammation signaling pathway. Acupuncture regulates the pathway at different levels by regulating several key nodal proteins, including downregulating of proinflammatory proteins (e.g., S100A8, RAGE, and S100A11 and upregulating of anti-inflammatory proteins (e.g., CC10, ANXA5, and sRAGE. These deregulated inflammation-related proteins may mediate, at least in part, the antiasthmatic effect of acupuncture. Further functional investigation of these acupuncture-specific effector proteins could identify new drug candidates for the prophylaxis and treatment of asthma.

  5. SLIT2 attenuation during lung cancer progression deregulates beta-catenin and E-cadherin and associates with poor prognosis.

    Science.gov (United States)

    Tseng, Ruo-Chia; Lee, Shih-Hua; Hsu, Han-Shui; Chen, Ben-Han; Tsai, Wan-Ching; Tzao, Ching; Wang, Yi-Ching

    2010-01-15

    Chromosome 4p15.3 is frequently deleted in late-stage lung cancer. We investigated the significance of the SLIT2 gene located in this region to lung cancer progression. SLIT2 encodes an extracellular glycoprotein that can suppress breast cancer by regulating beta-catenin. In this study, we examined alterations in the structure or expression of SLIT2, its receptor ROBO1, and beta-catenin, along with the AKT/glycogen synthase kinase 3beta (GSK3beta)/beta-transducin repeat-containing protein (betaTrCP) pathway in lung cancer cell lines and patients. Low SLIT2 expression correlated with an upward trend of pathological stage and poorer survival in lung cancer patients. Importantly, SLIT2, betaTrCP, and beta-catenin expression levels predicted postoperative recurrence of lung cancer in patients. Stimulating SLIT2 expression by various methods increased the level of E-cadherin caused by attenuation of its transcriptional repressor SNAI1. Conversely, knocking down SLIT2 expression increased cell migration and reduced cell adhesion through coordinated deregulation of beta-catenin and E-cadherin/SNAI1 in the AKT/GSK3beta/betaTrCP pathway. Our findings indicate that SLIT2 suppresses lung cancer progression, defining it as a novel "theranostic" factor with potential as a therapeutic target and prognostic predictor in lung cancer. Cancer Res; 70(2); 543-51.

  6. Proteomic Analysis Reveals the Deregulation of Inflammation-Related Proteins in Acupuncture-Treated Rats with Asthma Onset

    Science.gov (United States)

    Xu, Yu-Dong; Cui, Jian-Mei; Wang, Yu; Yin, Lei-Miao; Gao, Chang-Ke; Liu, Xiao-Yan; Wei, Ying; Liu, Yan-Yan; Jiang, Yong-Liang; Shan, Chun-Xiao; Yang, Yong-Qing

    2012-01-01

    Although the beneficial effects of acupuncture in asthma treatment have been well documented, little is known regarding the biological basis of this treatment. Changes in the lung proteome of acupuncture-treated rats with asthma onset were comparatively analyzed using a two-dimensional gel electrophoresis (2DE) and mass-spectrometry- (MS-) based proteomic approach. Acupuncture on specific acupuncture points appeared to improve respiratory function and reduce the total number of leukocytes and eosinophils in bronchoalveolar lavage fluid in OVA-induced asthma onset. Image analysis of 2DE gels revealed 32 differentially expressed acupuncture-specific protein spots in asthma onset; 30 of which were successfully identified as 28 unique proteins using LC-MS/MS. Bioinformatic analyses indicated that these altered proteins are most likely involved in inflammation-related biological functions, and the functional associations of these proteins result in an inflammation signaling pathway. Acupuncture regulates the pathway at different levels by regulating several key nodal proteins, including downregulating of proinflammatory proteins (e.g., S100A8, RAGE, and S100A11) and upregulating of anti-inflammatory proteins (e.g., CC10, ANXA5, and sRAGE). These deregulated inflammation-related proteins may mediate, at least in part, the antiasthmatic effect of acupuncture. Further functional investigation of these acupuncture-specific effector proteins could identify new drug candidates for the prophylaxis and treatment of asthma. PMID:23304218

  7. Marketing of Nicotine Replacement Therapy Products in a Deregulated Swedish Pharmacy Market

    OpenAIRE

    Tozlikian, Shant; Falk, Erik

    2009-01-01

                    The thesis will provide a description of the previous Swedish NRT marketing mix, a description of the present plans of Swedish NRT marketers for the marketing mix of their products, and the present marketing mix of the previously deregulated pharmacy markets in Finland and Norway. The purpose is to develop conclusions on how marketers of NRT products could change their marketing mix in response to the deregulation of the Swedish pharmacy market.    This thesis relies on a des...

  8. Heredity in fundamental left complemented algebras

    Directory of Open Access Journals (Sweden)

    Marina Haralampidou

    2016-06-01

    Full Text Available In the present paper, we introduce the notion of a fundamental complemented linear space, through continuous projections. This notion is hereditary. Relative to this, we prove that if a certain topological algebra is fundamental, then a concrete subspace is fundamental too. For a fundamental complemented linear space, we define the notion of continuity of the complementor. In some cases, we employ a generalized notion of complementation, that of (left precomplementation. In our main result, the continuity of the complementor for a certain fundamental complemented (topological algebra is inherited to the induced vector complementor of the underlying linear space of a certain right ideal. Weakly fundamental algebras are also considered in the context of locally convex ones.

  9. Evolution of the complement system in protostomes revealed by de novo transcriptome analysis of six species of Arthropoda.

    Science.gov (United States)

    Sekiguchi, Reo; Nonaka, Masaru

    2015-05-01

    To elucidate the evolutionary history of the complement system in Arthropoda, de novo transcriptome analysis was performed with six species among the Chelicerata, Myriapoda, and Crustacea, and complement genes were identified based on their characteristic domain structures. Complement C3 and factor B (FB) were identified from a sea spider, a jumping spider, and a centipede, but not from a sea firefly or two millipede species. No additional complement components identifiable by their characteristic domain structures were found from any of these six species. These results together with genome sequence information for several species of the Hexapoda suggest that the common ancestor of the Arthropoda possessed a simple complement system comprising C3 and FB, and thus resembled the alternative pathway of the mammalian complement system. It was lost at least twice independently during the evolution of Arthropoda in the millipede lineage and in the common ancestor of Crustacea and Hexapoda.

  10. Complement activation and inhibition: a delicate balance

    DEFF Research Database (Denmark)

    Sjöberg, A P; Trouw, L A; Blom, A M

    2009-01-01

    Complement is part of the innate immune defence and not only recognizes microbes but also unwanted host molecules to enhance phagocytosis and clearance. This process of opsonisation must be tightly regulated to prevent immunopathology. Endogenous ligands such as dying cells, extracellular matrix...... activation. Disturbances to the complement regulation on endogenous ligands can lead to diseases such as age-related macular degeneration, neurological and rheumatic disorders. A thorough understanding of these processes might be crucial to developing new therapeutic strategies....

  11. Efficacy of Targeted Complement Inhibition in Experimental C3 Glomerulopathy

    Science.gov (United States)

    Ruseva, Marieta M.; Peng, Tao; Lasaro, Melissa A.; Bouchard, Keith; Liu-Chen, Susan; Sun, Fang; Yu, Zhao-Xue; Marozsan, Andre; Wang, Yi

    2016-01-01

    C3 glomerulopathy refers to renal disorders characterized by abnormal accumulation of C3 within the kidney, commonly along the glomerular basement membrane (GBM). C3 glomerulopathy is associated with complement alternative pathway dysregulation, which includes functional defects in complement regulator factor H (FH). There is no effective treatment for C3 glomerulopathy. We investigated the efficacy of a recombinant mouse protein composed of domains from complement receptor 2 (CR2) and FH (CR2-FH) in two models of C3 glomerulopathy with either preexisting or triggered C3 deposition along the GBM. FH-deficient mice spontaneously develop renal pathology associated with abnormal C3 accumulation along the GBM and secondary plasma C3 deficiency. CR2-FH partially restored plasma C3 levels in FH-deficient mice 2 hours after intravenous injection. CR2-FH specifically targeted glomerular C3 deposits, reduced the linear C3 reactivity assessed with anti-C3 and anti-C3b/iC3b/C3c antibodies, and prevented further spontaneous accumulation of C3 fragments along the GBM. Reduction in glomerular C3d and C9/C5b-9 reactivity was observed after daily administration of CR2-FH for 1 week. In a second mouse model with combined deficiency of FH and complement factor I, CR2-FH prevented de novo C3 deposition along the GBM. These data show that CR2-FH protects the GBM from both spontaneous and triggered C3 deposition in vivo and indicate that this approach should be tested in C3 glomerulopathy. PMID:26047789

  12. Role of complement in neurodegeneration and neuroinflammation.

    Science.gov (United States)

    Bonifati, Domenico Marco; Kishore, Uday

    2007-02-01

    The complement system provides an innate defence mechanism against pathogenic microorganisms. Although viewed for many years as an immune-privileged organ, the central nervous system contains many components of the immune system, including components of the complement system that are synthesized by astrocytes, microglia, and neurons. During the past two decades, a wide range of inflammatory markers, typically absent in the normal elderly population, have been reported in Alzheimer's disease brains. It is becoming evident that sustained brain inflammation might be an essential cofactor in Alzheimer disease and other neurodegenerative disorders such as Parkinson disease, dementia with Lewy bodies, Huntington's and prion diseases. The complement system may be useful in eliminating aggregated and toxic proteins associated with these neurological disorders and thus have a protective effect. However, an exaggerated or insufficient activation of the complement system can have deleterious effect through the activation of microglia, secretion of many proinflammatory cytokines, and generation of oxidative products. The role of complement-mediated inflammation in Alzheimer disease has drawn greater attention recently in view of new therapeutic advances made in the management of the disease. This review is meant to update the role of complement in Alzheimer's disease and other neurodegenerative disorders in view of recent vaccination and immunotherapeutic approaches.

  13. Complement and thrombosis in the antiphospholipid syndrome.

    Science.gov (United States)

    Oku, Kenji; Nakamura, Hiroyuki; Kono, Michihiro; Ohmura, Kazumasa; Kato, Masaru; Bohgaki, Toshiyuki; Horita, Tetsuya; Yasuda, Shinsuke; Amengual, Olga; Atsumi, Tatsuya

    2016-10-01

    The involvement of complement activation in the pathophysiology of antiphospholipid syndrome (APS) was first reported in murine models of antiphospholipid antibody (aPL)-related pregnancy morbidities. We previously reported that complement activation is prevalent and may function as a source of procoagulant cell activation in the sera of APS patients. Recently, autoantibodies against C1q, a component of complement 1, were reported to be correlated with complement activation in systemic lupus erythematosus. These antibodies target neoepitopes of deformed C1q bound to various molecules (i.e., anionic phospholipids) and induce accelerated complement activation. We found that anti-C1q antibodies are more frequently detected in primary APS patients than in control patients and in refractory APS patients with repeated thrombotic events. The titer of anti-C1q antibodies was significantly higher in refractory APS patients than in APS patients without flare. The binding of C1q to anionic phospholipids may be associated with the surge in complement activation in patients with anti-C1q antibodies when triggered by 'second-hit' biological stressors such as infection. Such stressors will induce overexpression of anionic phospholipids, with subsequent increases in deformed C1q that is targeted by anti-C1q antibodies.

  14. Mechanisms of complement activation by dextran-coated superparamagnetic iron oxide (SPIO) nanoworms in mouse versus human serum

    DEFF Research Database (Denmark)

    Banda, Nirmal K; Mehta, Gaurav; Chao, Ying

    2014-01-01

    BACKGROUND: The complement system is a key component of innate immunity implicated in the neutralization and clearance of invading pathogens. Dextran coated superparamagnetic iron oxide (SPIO) nanoparticle is a promising magnetic resonance imaging (MRI) contrast agent. However, dextran SPIO has...... pathway (LP) or alternative pathway (AP) components were used to study mechanisms of mouse complement activation. In vitro measurements of fluid phase markers of complement activation C4d and Bb and the terminal pathway marker SC5b-C9 in normal and genetically deficient sera were used to study...... the CP, but that did not affect the total level of C3 deposition on the particles. CONCLUSIONS: There were important differences and similarities in the complement activation by SPIO NW in mouse versus human sera. Understanding the mechanisms of immune recognition of nanoparticles in mouse and human...

  15. Recruitment of Factor H as a Novel Complement Evasion Strategy for Blood-Stage Plasmodium falciparum Infection.

    Science.gov (United States)

    Kennedy, Alexander T; Schmidt, Christoph Q; Thompson, Jennifer K; Weiss, Greta E; Taechalertpaisarn, Tana; Gilson, Paul R; Barlow, Paul N; Crabb, Brendan S; Cowman, Alan F; Tham, Wai-Hong

    2016-02-01

    The human complement system is the frontline defense mechanism against invading pathogens. The coexistence of humans and microbes throughout evolution has produced ingenious molecular mechanisms by which microorganisms escape complement attack. A common evasion strategy used by diverse pathogens is the hijacking of soluble human complement regulators to their surfaces to afford protection from complement activation. One such host regulator is factor H (FH), which acts as a negative regulator of complement to protect host tissues from aberrant complement activation. In this report, we show that Plasmodium falciparum merozoites, the invasive form of the malaria parasites, actively recruit FH and its alternative spliced form FH-like protein 1 when exposed to human serum. We have mapped the binding site in FH that recognizes merozoites and identified Pf92, a member of the six-cysteine family of Plasmodium surface proteins, as its direct interaction partner. When bound to merozoites, FH retains cofactor activity, a key function that allows it to downregulate the alternative pathway of complement. In P. falciparum parasites that lack Pf92, we observed changes in the pattern of C3b cleavage that are consistent with decreased regulation of complement activation. These results also show that recruitment of FH affords P. falciparum merozoites protection from complement-mediated lysis. Our study provides new insights on mechanisms of immune evasion of malaria parasites and highlights the important function of surface coat proteins in the interplay between complement regulation and successful infection of the host.

  16. Assembly and activation of alternative complement components on endothelial cell-anchored ultra-large von Willebrand factor links complement and hemostasis-thrombosis.

    Directory of Open Access Journals (Sweden)

    Nancy A Turner

    Full Text Available BACKGROUND: Vascular endothelial cells (ECs express and release protein components of the complement pathways, as well as secreting and anchoring ultra-large von Willebrand factor (ULVWF multimers in long string-like structures that initiate platelet adhesion during hemostasis and thrombosis. The alternative complement pathway (AP is an important non-antibody-requiring host defense system. Thrombotic microangiopathies can be associated with defective regulation of the AP (atypical hemolytic-uremic syndrome or with inadequate cleavage by ADAMTS-13 of ULVWF multimeric strings secreted by/anchored to ECs (thrombotic thrombocytopenic purpura. Our goal was to determine if EC-anchored ULVWF strings caused the assembly and activation of AP components, thereby linking two essential defense mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: We quantified gene expression of these complement components in cultured human umbilical vein endothelial cells (HUVECs by real-time PCR: C3 and C5; complement factor (CF B, CFD, CFP, CFH and CFI of the AP; and C4 of the classical and lectin (but not alternative complement pathways. We used fluorescent microscopy, monospecific antibodies against complement components, fluorescent secondary antibodies, and the analysis of >150 images to quantify the attachment of HUVEC-released complement proteins to ULVWF strings secreted by, and anchored to, the HUVECs (under conditions of ADAMTS-13 inhibition. We found that HUVEC-released C4 did not attach to ULVWF strings, ruling out activation of the classical and lectin pathways by the strings. In contrast, C3, FB, FD, FP and C5, FH and FI attached to ULVWF strings in quantitative patterns consistent with assembly of the AP components into active complexes. This was verified when non-functional FB blocked the formation of AP C3 convertase complexes (C3bBb on ULVWF strings. CONCLUSIONS/SIGNIFICANCE: AP components are assembled and activated on EC-secreted/anchored ULVWF multimeric

  17. Complement emerges as a masterful regulator of CNS homeostasis, neural synaptic plasticity and cognitive function.

    Science.gov (United States)

    Mastellos, Dimitrios C

    2014-11-01

    Growing evidence points to a previously elusive role of complement-modulated pathways in CNS development, neurogenesis and synaptic plasticity. Distinct complement effectors appear to play a multifaceted role in brain homeostasis by regulating synaptic pruning in the retinogeniculate system and sculpting functional neural circuits both in the developing and adult mammalian brain. A recent study by Perez-Alcazar et al. (2014) provides novel insights into this intricate interplay between complement and the dynamically regulated brain synaptic circuitry, by reporting that mice deficient in C3 exhibit enhanced hippocampus-dependent spatial learning and cognitive performance. This behavioral pattern is associated with an impact of C3 on the functional capacity of glutamatergic synapses, supporting a crucial role for complement in excitatory synapse elimination in the hippocampus. These findings add a fresh twist to this rapidly evolving research field, suggesting that discrete complement components may differentially modulate synaptic connectivity by wiring up with diverse neural effectors in different regions of the brain. The emerging role of complement in synaptogenesis and neural network plasticity opens new conceptual avenues for considering complement interception as a potential therapeutic modality for ameliorating progressive cognitive impairment in age-related, debilitating brain diseases with a prominent inflammatory signature.

  18. Direct evidence of complement activation in HELLP syndrome: A link to atypical hemolytic uremic syndrome.

    Science.gov (United States)

    Vaught, Arthur J; Gavriilaki, Eleni; Hueppchen, Nancy; Blakemore, Karin; Yuan, Xuan; Seifert, Sara M; York, Sarah; Brodsky, Robert A

    2016-05-01

    HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) is a severe variant of pre-eclampsia whose pathogenesis remains unclear. Recent evidence and clinical similarities suggest a link to atypical hemolytic uremic syndrome, a disease of excessive activation of the alternative complement pathway effectively treated with a complement inhibitor, eculizumab. Therefore, we used a functional complement assay, the modified Ham test, to analyze sera of women with classic or atypical HELLP syndrome, pre-eclampsia with severe features, normal pregnancies, and healthy nonpregnant women. Sera were also evaluated using levels of the terminal product of complement activation (C5b-9). We tested the in vitro ability of eculizumab to inhibit complement activation in HELLP serum. Increased complement activation was observed in participants with classic or atypical HELLP compared with those with normal pregnancies and nonpregnant controls. Mixing HELLP serum with eculizumab-containing serum resulted in a significant decrease in cell killing compared with HELLP serum alone. We found that HELLP syndrome is associated with increased complement activation as assessed with the modified Ham test. This assay may aid in the diagnosis of HELLP syndrome and could confirm that its pathophysiology is related to that of atypical hemolytic uremic syndrome.

  19. Development of a large scale human complement source for use in bacterial immunoassays.

    Science.gov (United States)

    Brookes, Charlotte; Kuisma, Eeva; Alexander, Frances; Allen, Lauren; Tipton, Thomas; Ram, Sanjay; Gorringe, Andrew; Taylor, Stephen

    2013-05-31

    The serum bactericidal assay is the correlate of protection for meningococcal disease but the use and comparison of functional immunological assays for the assessment of meningococcal vaccines is complicated by the sourcing of human complement. This is due to high levels of immunity in the population acquired through natural meningococcal carriage and means that many individuals must be screened to find donors with suitably low bactericidal titres against the target strain. The use of different donors for each meningococcal strain means that comparisons of assay responses between strains and between laboratories is difficult. We have developed a method for IgG-depletion of 300 ml batches of pooled human lepirudin-derived plasma using Protein G sepharose affinity chromatography that retains complement activity. However, IgG-depletion also removed C1q. This was also eluted from the affinity matrix, concentrated and added to the complement source. The final complement source retained mean alternative pathway activity of 96.8% and total haemolytic activity of 84.2% in four batches. Complement components C3, C5, properdin and factor H were retained following the process and the IgG-depleted complement was shown to be suitable for use in antibody-mediated complement deposition and serum bactericidal activity assays against serogroup B meningococci. The generation of large IgG-depleted batches of pooled human plasma allows for the comparison of immunological responses to diverse meningococcal strain panels in large clinical trials.

  20. Inhibition of aberrant complement activation by a dimer of acetylsalicylic acid.

    Science.gov (United States)

    Lee, Moonhee; Wathier, Matthew; Love, Jennifer A; McGeer, Edith; McGeer, Patrick L

    2015-10-01

    We here report synthesis for the first time of the acetyl salicylic acid dimer 5,5'-methylenebis(2-acetoxybenzoic acid) (DAS). DAS inhibits aberrant complement activation by selectively blocking factor D of the alternative complement pathway and C9 of the membrane attack complex. We have previously identified aurin tricarboxylic and its oligomers as promising agents in this regard. DAS is much more potent, inhibiting erythrocyte hemolysis by complement-activated serum with an IC50 in the 100-170 nanomolar range. There are numerous conditions where self-damage from the complement system has been implicated in the pathology, including such chronic degenerative diseases of aging as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and age-related macular degeneration. Consequently, there is a high priority for the discovery and development of agents that can successfully treat such conditions. DAS holds considerable promise for being such an agent.

  1. Modeling cancer progression via pathway dependencies.

    Directory of Open Access Journals (Sweden)

    Elena J Edelman

    2008-02-01

    Full Text Available Cancer is a heterogeneous disease often requiring a complexity of alterations to drive a normal cell to a malignancy and ultimately to a metastatic state. Certain genetic perturbations have been implicated for initiation and progression. However, to a great extent, underlying mechanisms often remain elusive. These genetic perturbations are most likely reflected by the altered expression of sets of genes or pathways, rather than individual genes, thus creating a need for models of deregulation of pathways to help provide an understanding of the mechanisms of tumorigenesis. We introduce an integrative hierarchical analysis of tumor progression that discovers which a priori defined pathways are relevant either throughout or in particular steps of progression. Pathway interaction networks are inferred for these relevant pathways over the steps in progression. This is followed by the refinement of the relevant pathways to those genes most differentially expressed in particular disease stages. The final analysis infers a gene interaction network for these refined pathways. We apply this approach to model progression in prostate cancer and melanoma, resulting in a deeper understanding of the mechanisms of tumorigenesis. Our analysis supports previous findings for the deregulation of several pathways involved in cell cycle control and proliferation in both cancer types. A novel finding of our analysis is a connection between ErbB4 and primary prostate cancer.

  2. Dimerization of complement factor H-related proteins modulates complement activation in vivo.

    Science.gov (United States)

    Goicoechea de Jorge, Elena; Caesar, Joseph J E; Malik, Talat H; Patel, Mitali; Colledge, Matthew; Johnson, Steven; Hakobyan, Svetlana; Morgan, B Paul; Harris, Claire L; Pickering, Matthew C; Lea, Susan M

    2013-03-19

    The complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the complement factor H-related (CFHR) locus. Elucidating the mechanism underlying these associations has been hindered by the lack of understanding of the biological role of CFHR proteins. Here we present unique structural data demonstrating that three of the CFHR proteins contain a shared dimerization motif and that this hitherto unrecognized structural property enables formation of both homodimers and heterodimers. Dimerization confers avidity for tissue-bound complement fragments and enables these proteins to efficiently compete with the physiological complement inhibitor, complement factor H (CFH), for ligand binding. Our data demonstrate that these CFHR proteins function as competitive antagonists of CFH to modulate complement activation in vivo and explain why variation in the CFHRs predisposes to disease.

  3. The epidermal growth factor receptor is a regulator of epidermal complement component expression and complement activation

    DEFF Research Database (Denmark)

    Abu-Humaidan, Anas H A; Ananthoju, Nageshwar; Mohanty, Tirthankar;

    2014-01-01

    The complement system is activated in response to tissue injury. During wound healing, complement activation seems beneficial in acute wounds but may be detrimental in chronic wounds. We found that the epidermal expression of many complement components was only increased to a minor extent in skin...... wounds in vivo and in cultured keratinocytes after exposure to supernatant from stimulated mononuclear cells. In contrast, the epidermal expression of complement components was downregulated in ex vivo injured skin lacking the stimulation from infiltrating inflammatory cells but with intact injury......-induced epidermal growth factor receptor (EGFR)-mediated growth factor response. In cultured primary keratinocytes, stimulation with the potent EGFR ligand, TGF-α, yielded a significant downregulation of complement component expression. Indeed, EGFR inhibition significantly enhanced the induction of complement...

  4. 75 FR 62365 - Monsanto Company and KWS SAAT AG; Supplemental Request for Partial Deregulation of Roundup Ready...

    Science.gov (United States)

    2010-10-08

    ... for the Northern District of California issued a ruling in a lawsuit filed by two organic seed groups and two nonprofit organizations challenging our decision to deregulate sugar beet event H7-1 (referred... making a decision on the supplemental petition for ``partial deregulation'' and on other appropriate...

  5. New perspectives on mannan-binding lectin-mediated complement activation

    DEFF Research Database (Denmark)

    Degn, Søren Egedal; Thiel, Steffen; Jensenius, Jens Christian

    2007-01-01

    is the most recently discovered, and least characterized. The CP and the LP are generally viewed as working through the generation of the C3 convertase, C4bC2b, and are here referred to as the "standard" pathways. In addition to the standard CP and LP, so-called bypass pathways have also been reported...... picture of the complement system is more that of a small "scale-free" network where C3 acts as the main hub, than that of three linear pathways converging in a common terminal pathway....

  6. Nonalcoholic Fatty Liver Disease: Focus on Lipoprotein and Lipid Deregulation

    Directory of Open Access Journals (Sweden)

    Klementina Fon Tacer

    2011-01-01

    Full Text Available Obesity with associated comorbidities is currently a worldwide epidemic and among the most challenging health conditions in the 21st century. A major metabolic consequence of obesity is insulin resistance which underlies the pathogenesis of the metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD is the hepatic manifestation of obesity and metabolic syndrome. It comprises a disease spectrum ranging from simple steatosis (fatty liver, through nonalcoholic steatohepatitis (NASH to fibrosis, and ultimately liver cirrhosis. Abnormality in lipid and lipoprotein metabolism accompanied by chronic inflammation is the central pathway for the development of metabolic syndrome-related diseases, such as atherosclerosis, cardiovascular disease (CVD, and NAFLD. This paper focuses on pathogenic aspect of lipid and lipoprotein metabolism in NAFLD and the relevant mouse models of this complex multifactorial disease.

  7. Overview of the developments in the domestic airline industry in South Africa since market deregulation

    National Research Council Canada - National Science Library

    Luke, Rose; Walters, Jackie

    2013-01-01

    ... immediately following deregulation led to a flurry of airline entries and exits. Following the entry of the first low-cost carrier in 2001, the structure of the market has changed significantly, with the low-cost carriers appearing to have the effect of stimulating the market and creating growth in passenger numbers, increasing load factors and ai...

  8. Internationalization, Deregulation and the Expansion of Higher Education in Korea: An Historical Overview

    Science.gov (United States)

    Green, Christopher

    2015-01-01

    The purpose of this article is to provide an overview of internationalization policies in Korean higher education since 1993. Deregulation was a key strategy of Korean governments, but this strategy has led to an increasing oversupply of enrolment capacity. In response, the current government is implementing a system of reregulation to reduce the…

  9. The energy markets deregulation; L'ouverture des marches de l'energie

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-07-01

    This document is devoted to the opening of the energy markets and the associated production forms. The deregulation is going to change the technology with the need of a global answer to the the energy demands of the manufacturers and the local governments. In this context, the nuclear pole in the world facing the other forms of energy is discussed. (A.L.B.)

  10. EFFECTS OF INTEREST RATE DEREGULATION ON AGRICULTURAL FINANCE AND GROWTH IN NIGERIA

    Directory of Open Access Journals (Sweden)

    Louis O. ONYISHI

    2015-03-01

    Full Text Available The study examined the effects of interest rate deregulation on agricultural finance and growth in Nigeria. The study specifically ascertained the factors that determine the aggregate credit volume to agriculture within the periods of regulation and deregulation in the Nigerian economy, determined the effects of government finance interventions on agricultural sector performance in the Nigerian economy, determined the periodic effects of macroeconomic financial indicators on Agriculture’s gross domestic product (GDP contribution to Nigerian economy and estimated the level of real credit growth of agricultural finance in Nigeria. Descriptive statistics, Ordinary Least Squares (OLS regression technique and chow test were used for data analysis. The chow test showed that there was a significant differential effect on the aggregate credit volume to agricultural sector between the regulated and deregulated regimes. Interest rate was an important determinant of aggregate credit volume to the agricultural sector in Nigeria, especially during the deregulated period but monetary authorities should ensure appropriate determination of interest rate level that will break the double-edge effect of interest rates on savers and investors.

  11. Internationalization, Deregulation and the Extension of Higher Education in Korea: A Further Note

    Science.gov (United States)

    Jin, Jang C.

    2015-01-01

    The Korean government implemented several educational policies to enhance internationalization of higher education such as deregulation of higher education, classroom instructions in English, and faculty publications in international refereed journals. However, the speed of globalization has been lagging behind (Green, 2015). Alternatively, this…

  12. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia

    NARCIS (Netherlands)

    Gröschel, Stefan; Sanders, Mathijs A; Hoogenboezem, Remco; de Wit, Elzo; Bouwman, Britta A M; Erpelinck, Claudia; van der Velden, Vincent H J; Havermans, Marije; Avellino, Roberto; van Lom, Kirsten; Rombouts, Elwin J; van Duin, Mark; Döhner, Konstanze; Beverloo, H Berna; Bradner, James E; Döhner, Hartmut; Löwenberg, Bob; Valk, Peter J M; Bindels, Eric M J; de Laat, Wouter; Delwel, Ruud

    2014-01-01

    Chromosomal rearrangements without gene fusions have been implicated in leukemogenesis by causing deregulation of proto-oncogenes via relocation of cryptic regulatory DNA elements. AML with inv(3)/t(3;3) is associated with aberrant expression of the stem-cell regulator EVI1. Applying functional geno

  13. The Impact of Labour Market Deregulation: Lessons from the "Kiwi"and "Polder" Models

    NARCIS (Netherlands)

    Gorter, Cees; Poot, Jacques

    1999-01-01

    Unemployment remains a major economic and social problem in many developedeconomies. This paper provides theoretical and empirical perspectives on the impact of labour market deregulation as a means of combatting unemployment and of enhancing competitive wage determination. The paper focusses specif

  14. Complement in therapy and disease: Regulating the complement system with antibody-based therapeutics.

    Science.gov (United States)

    Melis, Joost P M; Strumane, Kristin; Ruuls, Sigrid R; Beurskens, Frank J; Schuurman, Janine; Parren, Paul W H I

    2015-10-01

    Complement is recognized as a key player in a wide range of normal as well as disease-related immune, developmental and homeostatic processes. Knowledge of complement components, structures, interactions, and cross-talk with other biological systems continues to grow and this leads to novel treatments for cancer, infectious, autoimmune- or age-related diseases as well as for preventing transplantation rejection. Antibodies are superbly suited to be developed into therapeutics with appropriate complement stimulatory or inhibitory activity. Here we review the design, development and future of antibody-based drugs that enhance or dampen the complement system.

  15. Synergy between ficolin-2 and pentraxin 3 boosts innate immune recognition and complement deposition

    DEFF Research Database (Denmark)

    Ma, Ying Jie; Doni, Andrea; Hummelshøj, Tina;

    2009-01-01

    The long pentraxin 3 (PTX3) is a multifunctional soluble pattern recognition molecule that is crucial in innate immune protection against opportunistic fungal pathogens such as Aspergillus fumigatus. The mechanisms that mediate downstream effects of PTX3 are largely unknown. However, PTX3 interacts...... with C1q from the classical pathway of the complement. The ficolins are recognition molecules of the lectin complement pathway sharing structural and functional characteristics with C1q. Thus, we investigated whether the ficolins (Ficolin-1, -2, and -3) interact with PTX3 and whether the complexes....... fumigatus directly, but this binding was enhanced by PTX3 and vice versa. Ficolin-2-dependent complement deposition on the surface of A. fumigatus was enhanced by PTX3. A polymorphism in the FCN2 gene causing a T236M amino acid change in the fibrinogen-like binding domain of Ficolin-2, which affects...

  16. Why electricity deregulation is likely to fail: An explanation with an application to Israel

    Energy Technology Data Exchange (ETDEWEB)

    Tishler, Asher; Woo, Chi-Keung

    2005-12-15

    In this paper we contend that electricity deregulation likely fails because of a fundamental, but so far ignored, reason. In particular, a deregulated electricity market cannot have too many producers because they will not be able to recover their investment costs. Nor can it have too few producers because the resulting market price will likely exceed the regulated rate. If constrained by the financial viability of privately owned generators and an overarching goal of unregulated market price not exceeding the regulated rate, the set of feasible numbers of producers in the competitive market can be very small, and at times empty. Our theoretical prediction applies to deregulation of other industries with large fixed and sunk costs (e.g., gas transportation, electricity transmission and distribution, local telecom networks, ports, railways, etc.). We show that a large improvement in the operational efficiency of the deregulated industry is a necessary condition for a successful deregulation of the industry. Unfortunately, operation improvement in electricity generation is limited because fuel (e.g., coal, oil, natural gas, and liquefied natural gas) and generation equipment (e.g., turbines, transformers, and cables), which constitute about 80% of the total cost of electricity generation, are commodities traded in a competitive world market. Thus, cost savings due to deregulation in the electricity generation market mainly come from efficiency improvement in capacity investment and variable input use of labor and O and M. Unless the regulated integrated utility has been investing inefficiently in surplus capacity, such savings, mainly in labor and O and M, are unlikely to produce more than a 10% reduction in total generation cost. For this reason and based on the experience to date, we caution against deregulation in regions that currently have a regulated electricity sector (e.g., China, India, Hong Kong, Israel, Africa, and many parts of North America). Our

  17. Interaction between human complement and a pectin type polysaccharide fraction, PMII, from the leaves of Plantago major L.

    Science.gov (United States)

    Michaelsen, T E; Gilje, A; Samuelsen, A B; Høgåsen, K; Paulsen, B S

    2000-11-01

    The interaction between a pectin type polysaccharide fraction, PMII, isolated from the leaves of Plantago major, and human complement was tested in two different hemolytic complement-fixation tests and in addition by two ELISA methods detecting complement-activation products. Sera were used as a complement source of 10 arbitrary human volunteers, individually and as a pool. The complement-fixation tests were designed to measure the concentration of the pectin necessary to inhibit 50% of the hemolysis (ICH(50)). The ELISA tests for complement-activation products were measured in AU/mg using a fully activated serum as a standard. We observed a more than 200-fold difference in ICH(50) activity of the PMII pectin in one of the hemolytic tests by varying the individual sera used as complement-source. On the other hand, the ELISA complement-activation tests showed no significant variation in activity of the PMII depending on the complement-serum used. The level of antibodies against PMII detected in the complement-sera did not correlate with the ICH(50) activity of PMII. The results show that PMII is a potent complement activator with an activity of the same order of magnitude on a weight basis as that of aggregated human immunoglobulin (Ig)G. This activation leads to a complement consumption probably explaining the PMII's effect in the complement-fixation tests. PMII seems to be an activator both on the classical and the alternative pathway of activation. The results might be related to the reported wound-healing effect of the leaves of Plantago major.

  18. University Staff’s Perception of Deregulation on Higher Education in Nigeria

    Directory of Open Access Journals (Sweden)

    Adebayo Florence Aduke

    2014-04-01

    Full Text Available The study investigated the university staff’s perception on deregulation of higher education in Nigeria. Descriptive research of the survey type was used for the study. The population comprised all the university staff of universities in Ekiti and Ondo states, Nigeria. Simple random sampling technique was used to select 700 academic and non-academic staff from the Federal and State universities in Ekiti and Ondo states. Research instrument designated University Staff Perception of Deregulation on Higher Education (USPDHE was used in collecting data. The questionnaire was subjected to face and content validity. The reliability co-efficient of the instrument was 0.75. The results showed that deregulation improved academic standard of the universities except in the areas of curriculum innovation and collaborative research and does not guarantee job security nor improve staff development and equity in salary structure but it contributed to managerial effectiveness, efficiency and accountability, It also showed that students were affected in the area of access to higher education, class structure, admission choice and exploitation by the institutions. It equally showed that deregulation is not improving the funding of higher institutions in Nigeria instead it throws the institution into dilemma of sourcing for fund. Some of the recommendations are: using management strategies at the institutional level, autonomy should use management strategies that emphasize improved standards in terms of improved curricula, and academic excellence by all and sundry within the system. Also, to have the full gains of deregulation, climate of academic integrity should be enshrined in the operation of the university system.

  19. The End of a Natural Monopoly. Deregulation and Competition in the Electric Power Industry

    Energy Technology Data Exchange (ETDEWEB)

    Grossman, P.Z. [Butler University, Indianapolis, IN 46208-3485 (United States); Cole, D.H. [Indiana University, Indianapolis, IN 46202-3225 (United States)

    2003-07-01

    For a hundred years, scholars and government officials understood, or thought they did, the electric power industry. Electric power, based on a single, large service provider, connected by wires to all of its customers, was thought to be an industry that could only operate efficiently as a monopoly; indeed it was something called a 'natural monopoly'. Since it had to be a monopoly, with all the attendant inefficiencies and potential market abuses monopoly entails, government regulation was necessary. These basic assumptions, which at times seemed to conflict with observed facts remained largely unquestioned for the better part of 75 years. Then, changing institutional and technological circumstances led economists to question the basis in fact of the theory of natural monopoly, and the regulatory system it entailed. Movement toward a deregulated electric power system began albeit in piece-meal fashion. Indeed, the result has been a crazy quilt of deregulation and re-regulations, which often have resulted in more costs than benefits for society as a whole. In the most infamous case, California, the entire enterprise of regulatory change has been called into question. The process of deregulation or reregulation in several other states has stopped because of fear of repeating California's mistakes. This book addresses some of the fundamental issues underlying the debate over electric power regulation and deregulation. Only by understanding these questions and exploring a variety of possible answers to them can we hope to move the debate over the proper structure of the electric power industry. Undoubtedly, electric power deregulation will be a major legal and economic concern for years to come.

  20. Review of MicroRNA Deregulation in Oral Cancer. Part I

    Directory of Open Access Journals (Sweden)

    Antonia Kolokythas

    2011-04-01

    Full Text Available Objectives: Oral cancer is the sixth most common malignancy worldwide. Cancer development and progression requires inactivation of tumour suppressor genes and activation of proto-oncogenes. Expression of these genes is in part dependant on RNA and microRNA based mechanisms. MicroRNAs are essential regulators of diverse cellular processes including proliferation, differentiation, apoptosis, survival, motility, invasion and morphogenesis. Several microRNAs have been found to be aberrantly expressed in various cancers including oral cancer.Material and Methods: A comprehensive review of the available literature from 2000 to 2011 relevant to microRNA deregulation in oral cancer was undertaken using PubMed, Medline, Scholar Google and Scopus. Keywords for the search were: microRNA and oral cancer, microRNA and squamous cell carcinoma, microRNA deregulation. Only full length articles in the English language were included. Strengths and limitations of each study are presented in this review.Results: Several studies were identified that investigated microRNA alternations in the head and neck/oral cavity cancers. Significant progress has been made in identification of microRNA deregulation in these cancers. It has been evident that several microRNAs were found to be deregulated specifically in oral cavity cancers. Among these, several microRNAs have been functionally validated and their potential target genes have been identified.Conclusions: These findings on microRNA deregulation in cancer further enhance our understanding of the disease progression, response to treatment and may assist with future development of targeted therapy.

  1. Inhibition of Complement Retards Ankylosing Spondylitis Progression

    Science.gov (United States)

    Yang, Chaoqun; Ding, Peipei; Wang, Qingkai; Zhang, Long; Zhang, Xin; Zhao, Jianquan; Xu, Enjie; Wang, Na; Chen, Jianfeng; Yang, Guang; Hu, Weiguo; Zhou, Xuhui

    2016-01-01

    Ankylosing spondylitis (AS) is a chronic axial spondyloarthritis (SpA) resulting in back pain and progressive spinal ankyloses. Currently, there are no effective therapeutics targeting AS largely due to elusive pathogenesis mechanisms, even as potential candidates such as HLA-B27 autoantigen have been identified. Herein, we employed a proteoglycan (PG)-induced AS mouse model together with clinical specimens, and found that the complement system was substantially activated in the spinal bone marrow, accompanied by a remarkable proportion alteration of neutrophils and macrophage in bone marrow and spleen, and by the significant increase of TGF-β1 in serum. The combined treatment with a bacteria-derived complement inhibitor Efb-C (C-terminal of extracellular fibrinogen-binding protein of Staphylococcus aureus) remarkably retarded the progression of mouse AS by reducing osteoblast differentiation. Furthermore, we demonstrated that two important modulators involved in AS disease, TGF-β1 and RANKL, were elevated upon in vitro complement attack in osteoblast and/or osteoclast cells. These findings further unravel that complement activation is closely related with the pathogenesis of AS, and suggest that complement inhibition may hold great potential for AS therapy. PMID:27698377

  2. Complement factor H related proteins (CFHRs).

    Science.gov (United States)

    Skerka, Christine; Chen, Qian; Fremeaux-Bacchi, Veronique; Roumenina, Lubka T

    2013-12-15

    Factor H related proteins comprise a group of five plasma proteins: CFHR1, CFHR2, CFHR3, CFHR4 and CFHR5, and each member of this group binds to the central complement component C3b. Mutations, genetic deletions, duplications or rearrangements in the individual CFHR genes are associated with a number of diseases including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathies (C3 glomerulonephritis (C3GN), dense deposit disease (DDD) and CFHR5 nephropathy), IgA nephropathy, age related macular degeneration (AMD) and systemic lupus erythematosus (SLE). Although complement regulatory functions were attributed to most of the members of the CFHR protein family, the precise role of each CFHR protein in complement activation and the exact contribution to disease pathology is still unclear. Recent publications show that CFHR proteins form homo- as well as heterodimers. Genetic abnormalities within the CFHR gene locus can result in hybrid proteins with affected dimerization or recognition domains which cause defective functions. Here we summarize the recent data about CFHR genes and proteins in order to better understand the role of CFHR proteins in complement activation and in complement associated diseases.

  3. X-ray repair cross complementing protein 1 in base excision repair

    DEFF Research Database (Denmark)

    Hanssen-Bauer, Audun; Solvang-Garten, Karin; Akbari, Mansour;

    2012-01-01

    X-ray Repair Cross Complementing protein 1 (XRCC1) acts as a scaffolding protein in the converging base excision repair (BER) and single strand break repair (SSBR) pathways. XRCC1 also interacts with itself and rapidly accumulates at sites of DNA damage. XRCC1 can thus mediate the assembly of large...

  4. Spontaneous complement activation on human B cells results in localized membrane depolarization and the clustering of complement receptor type 2 and C3 fragments

    DEFF Research Database (Denmark)

    Løbner, Morten; Leslie, Robert G Q; Prodinger, Wolfgang M

    2009-01-01

    While our previous studies have demonstrated that complement activation induced by complement receptors type 2 (CR2/CD21) and 1 (CR1/CD35) results in C3-fragment deposition and membrane attack complex (MAC) formation in human B cells, the consequences of these events for B-cell functions remain...... requires activation of complement via the alternative pathway, as indicated by total inhibition upon neutralization of factor D, and is abrogated by combined blockade of CR1 and CR2, but not of either receptor alone. The membrane depolarization is not associated with the apoptosis of B cells, as examined...... by co-staining with APO-2.7 or by the TdT-mediated biotin-dUTP nick-end labelling (TUNEL) assay. Confocal microscopy revealed that depolarization and C3 deposition, unlike MAC deposition, are limited to restricted areas on the B-cell surface. Double staining revealed a close association between the C3...

  5. De-regulation of common housekeeping genes in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Wurmbach Elisa

    2007-07-01

    Full Text Available Abstract Background Tumorigenesis is associated with changes in gene expression and involves many pathways. Dysregulated genes include "housekeeping" genes that are often used for normalization for quantitative real-time RT-PCR (qPCR, which may lead to unreliable results. This study assessed eight stages of hepatitis C virus (HCV induced hepatocellular carcinoma (HCC to search for appropriate genes for normalization. Results Gene expression profiles using microarrays revealed differential expression of most "housekeeping" genes during the course of HCV-HCC, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH and beta-actin (ACTB, genes frequently used for normalization. QPCR reactions confirmed the regulation of these genes. Using them for normalization had strong effects on the extent of differential expressed genes, leading to misinterpretation of the results. Conclusion As shown here in the case of HCV-induced HCC, the most constantly expressed gene is the arginine/serine-rich splicing factor 4 (SFRS4. The utilization of at least two genes for normalization is robust and advantageous, because they can compensate for slight differences of their expression when not co-regulated. The combination of ribosomal protein large 41 (RPL41 and SFRS4 used for normalization led to very similar results as SFRS4 alone and is a very good choice for reference in this disease as shown on four differentially expressed genes.

  6. Extremal Matching Energy of Complements of Trees

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    Wu Tingzeng

    2016-08-01

    Full Text Available Gutman and Wagner proposed the concept of the matching energy which is defined as the sum of the absolute values of the zeros of the matching polynomial of a graph. And they pointed out that the chemical applications of matching energy go back to the 1970s. Let T be a tree with n vertices. In this paper, we characterize the trees whose complements have the maximal, second-maximal and minimal matching energy. Furthermore, we determine the trees with edge-independence number p whose complements have the minimum matching energy for p = 1, 2, . . . , [n/2]. When we restrict our consideration to all trees with a perfect matching, we determine the trees whose complements have the second-maximal matching energy.

  7. Supramolecular Control over Split-Luciferase Complementation.

    Science.gov (United States)

    Bosmans, Ralph P G; Briels, Jeroen M; Milroy, Lech-Gustav; de Greef, Tom F A; Merkx, Maarten; Brunsveld, Luc

    2016-07-25

    Supramolecular split-enzyme complementation restores enzymatic activity and allows for on-off switching. Split-luciferase fragment pairs were provided with an N-terminal FGG sequence and screened for complementation through host-guest binding to cucurbit[8]uril (Q8). Split-luciferase heterocomplex formation was induced in a Q8 concentration dependent manner, resulting in a 20-fold upregulation of luciferase activity. Supramolecular split-luciferase complementation was fully reversible, as revealed by using two types of Q8 inhibitors. Competition studies with the weak-binding FGG peptide revealed a 300-fold enhanced stability for the formation of the ternary heterocomplex compared to binding of two of the same fragments to Q8. Stochiometric binding by the potent inhibitor memantine could be used for repeated cycling of luciferase activation and deactivation in conjunction with Q8, providing a versatile module for in vitro supramolecular signaling networks.

  8. Applying complement therapeutics to rare diseases.

    Science.gov (United States)

    Reis, Edimara S; Mastellos, Dimitrios C; Yancopoulou, Despina; Risitano, Antonio M; Ricklin, Daniel; Lambris, John D

    2015-12-01

    Around 350 million people worldwide suffer from rare diseases. These may have a genetic, infectious, or autoimmune basis, and several include an inflammatory component. Launching of effective treatments can be very challenging when there is a low disease prevalence and limited scientific insights into the disease mechanisms. As a key trigger of inflammatory processes, complement has been associated with a variety of diseases and has become an attractive therapeutic target for conditions involving inflammation. In view of the clinical experience acquired with drugs licensed for the treatment of rare diseases such as hereditary angioedema and paroxysmal nocturnal hemoglobinuria, growing evidence supports the safety and efficacy of complement therapeutics in restoring immune balance and preventing aggravation of clinical outcomes. This review provides an overview of the candidates currently in the pharmaceutical pipeline with potential to treat orphan diseases and discusses the molecular mechanisms triggered by complement involved with the disease pathogenesis.

  9. Targeting the TGFβ pathway for cancer therapy.

    Science.gov (United States)

    Neuzillet, Cindy; Tijeras-Raballand, Annemilaï; Cohen, Romain; Cros, Jérôme; Faivre, Sandrine; Raymond, Eric; de Gramont, Armand

    2015-03-01

    The TGFβ signaling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, motility and invasion, extracellular matrix production, angiogenesis, and immune response. TGFβ signaling deregulation is frequent in tumors and has crucial roles in tumor initiation, development and metastasis. TGFβ signaling inhibition is an emerging strategy for cancer therapy. The role of the TGFβ pathway as a tumor-promoter or suppressor at the cancer cell level is still a matter of debate, due to its differential effects at the early and late stages of carcinogenesis. In contrast, at the microenvironment level, the TGFβ pathway contributes to generate a favorable microenvironment for tumor growth and metastasis throughout all the steps of carcinogenesis. Then, targeting the TGFβ pathway in cancer may be considered primarily as a microenvironment-targeted strategy. In this review, we focus on the TGFβ pathway as a target for cancer therapy. In the first part, we provide a comprehensive overview of the roles played by this pathway and its deregulation in cancer, at the cancer cell and microenvironment levels. We go on to describe the preclinical and clinical results of pharmacological strategies to target the TGFβ pathway, with a highlight on the effects on tumor microenvironment. We then explore the perspectives to optimize TGFβ inhibition therapy in different tumor settings.

  10. The extracellular RNA complement of Escherichia coli.

    Science.gov (United States)

    Ghosal, Anubrata; Upadhyaya, Bimal Babu; Fritz, Joëlle V; Heintz-Buschart, Anna; Desai, Mahesh S; Yusuf, Dilmurat; Huang, David; Baumuratov, Aidos; Wang, Kai; Galas, David; Wilmes, Paul

    2015-01-21

    The secretion of biomolecules into the extracellular milieu is a common and well-conserved phenomenon in biology. In bacteria, secreted biomolecules are not only involved in intra-species communication but they also play roles in inter-kingdom exchanges and pathogenicity. To date, released products, such as small molecules, DNA, peptides, and proteins, have been well studied in bacteria. However, the bacterial extracellular RNA complement has so far not been comprehensively characterized. Here, we have analyzed, using a combination of physical characterization and high-throughput sequencing, the extracellular RNA complement of both outer membrane vesicle (OMV)-associated and OMV-free RNA of the enteric Gram-negative model bacterium Escherichia coli K-12 substrain MG1655 and have compared it to its intracellular RNA complement. Our results demonstrate that a large part of the extracellular RNA complement is in the size range between 15 and 40 nucleotides and is derived from specific intracellular RNAs. Furthermore, RNA is associated with OMVs and the relative abundances of RNA biotypes in the intracellular, OMV and OMV-free fractions are distinct. Apart from rRNA fragments, a significant portion of the extracellular RNA complement is composed of specific cleavage products of functionally important structural noncoding RNAs, including tRNAs, 4.5S RNA, 6S RNA, and tmRNA. In addition, the extracellular RNA pool includes RNA biotypes from cryptic prophages, intergenic, and coding regions, of which some are so far uncharacterised, for example, transcripts mapping to the fimA-fimL and ves-spy intergenic regions. Our study provides the first detailed characterization of the extracellular RNA complement of the enteric model bacterium E. coli. Analogous to findings in eukaryotes, our results suggest the selective export of specific RNA biotypes by E. coli, which in turn indicates a potential role for extracellular bacterial RNAs in intercellular communication. © 2015 The

  11. Role of complement receptor 1 (CR1; CD35) on epithelial cells: A model for understanding complement-mediated damage in the kidney.

    Science.gov (United States)

    Java, Anuja; Liszewski, M Kathryn; Hourcade, Dennis E; Zhang, Fan; Atkinson, John P

    2015-10-01

    The regulators of complement activation gene cluster encodes a group of proteins that have evolved to control the amplification of complement at the critical step of C3 activation. Complement receptor 1 (CR1) is the most versatile of these inhibitors with both receptor and regulatory functions. While expressed on most peripheral blood cells, the only epithelial site of expression in the kidney is by the podocyte. Its expression by this cell population has aroused considerable speculation as to its biologic function in view of many complement-mediated renal diseases. The goal of this investigation was to assess the role of CR1 on epithelial cells. To this end, we utilized a Chinese hamster ovary cell model system. Among our findings, CR1 reduced C3b deposition by ∼ 80% during classical pathway activation; however, it was an even more potent regulator (>95% reduction in C3b deposition) of the alternative pathway. This inhibition was primarily mediated by decay accelerating activity. The deposited C4b and C3b were progressively cleaved with a t½ of ∼ 30 min to C4d and C3d, respectively, by CR1-dependent cofactor activity. CR1 functioned intrinsically (i.e, worked only on the cell on which it was expressed). Moreover, CR1 efficiently and stably bound but didn't internalize C4b/C3b opsonized immune complexes. Our studies underscore the potential importance of CR1 on an epithelial cell population as both an intrinsic complement regulator and an immune adherence receptor. These results provide a framework for understanding how loss of CR1 expression on podocytes may contribute to complement-mediated damage in the kidney.

  12. Complement-mediated solubilization of immune complexes. Solubilization inhibition and complement factor levels in SLE patients

    DEFF Research Database (Denmark)

    Baatrup, Gunnar; Petersen, Ivan; Kappelgaard, E;

    1984-01-01

    Thirty-two of 36 serum samples from 19 SLE patients showed reduced capacity to mediate complement-dependent solubilization of immune complexes (IC). SLE patients with nephritis exerted the lowest complement-mediated solubilization capacity (CMSC) whereas sera from patients with inactive disease g...

  13. L^2-Betti numbers of hypersurface complements

    CERN Document Server

    Maxim, Laurentiu

    2012-01-01

    In \\cite{DJL07} it was shown that if $\\scra$ is an affine hyperplane arrangement in $\\C^n$, then at most one of the $L^2$--Betti numbers $b_i^{(2)}(\\C^n\\sm \\scra,\\id)$ is non--zero. In this note we prove an analogous statement for complements of complex affine hyperurfaces in general position at infinity. Furthermore, we recast and extend to this higher-dimensional setting results of \\cite{FLM,LM06} about $L^2$--Betti numbers of plane curve complements.

  14. HUS and the case for complement.

    Science.gov (United States)

    Conway, Edward M

    2015-10-29

    Hemolytic-uremic syndrome (HUS) is a thrombotic microangiopathy that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Excess complement activation underlies atypical HUS and is evident in Shiga toxin-induced HUS (STEC-HUS). This Spotlight focuses on new knowledge of the role of Escherichia coli-derived toxins and polyphosphate in modulating complement and coagulation, and how they affect disease progression and response to treatment. Such new insights may impact on current and future choices of therapies for STEC-HUS.

  15. Mesenchymal stromal cells engage complement and complement receptor bearing innate effector cells to modulate immune responses.

    Directory of Open Access Journals (Sweden)

    Guido Moll

    Full Text Available Infusion of human third-party mesenchymal stromal cells (MSCs appears to be a promising therapy for acute graft-versus-host disease (aGvHD. To date, little is known about how MSCs interact with the body's innate immune system after clinical infusion. This study shows, that exposure of MSCs to blood type ABO-matched human blood activates the complement system, which triggers complement-mediated lymphoid and myeloid effector cell activation in blood. We found deposition of complement component C3-derived fragments iC3b and C3dg on MSCs and fluid-phase generation of the chemotactic anaphylatoxins C3a and C5a. MSCs bound low amounts of immunoglobulins and lacked expression of complement regulatory proteins MCP (CD46 and DAF (CD55, but were protected from complement lysis via expression of protectin (CD59. Cell-surface-opsonization and anaphylatoxin-formation triggered complement receptor 3 (CD11b/CD18-mediated effector cell activation in blood. The complement-activating properties of individual MSCs were furthermore correlated with their potency to inhibit PBMC-proliferation in vitro, and both effector cell activation and the immunosuppressive effect could be blocked either by using complement inhibitor Compstatin or by depletion of CD14/CD11b-high myeloid effector cells from mixed lymphocyte reactions. Our study demonstrates for the first time a major role of the complement system in governing the immunomodulatory activity of MSCs and elucidates how complement activation mediates the interaction with other immune cells.

  16. Radioimmunoassay for anaphylatoxins: a sensitive method for determining complement activation products in biological fluids

    Energy Technology Data Exchange (ETDEWEB)

    Wagner, J.L.; Hugli, T.E.

    1984-01-01

    Activation of the blood complement system generates bioactive fragments called anaphylatoxins. The three anaphylatoxins C3a, C4a, and C5a are released during classical pathway activation while only C3a and C5a are released when the alternative pathway of complement is activated. Radioimmunoassays were designed to individually detect and quantitate the activation fragments C3a, C4a, and C5a in biological fluids without interference from the precursor molecules C3, C4, and C5. Kinetics of complement activation in fresh human serum exposed to the activators zymosan, heat-aggregated immunoglobulin, or cobra venom factor were monitored using the radioimmunoassay technique. For the first time, activation of components C3, C4, and C5 was followed simultaneously in a single serum sample. Analysis of the patterns and extent of anaphylatoxin formation during activation in serum may be used to screen for deficiencies or defects in the complement cascade. Levels of the anaphylatoxins in freshly drawn serum were much higher than levels detected in EDTA-plasma. Detection of low-level complement activation in patient's blood, urine, or synovial fluid, using anaphylatoxin formation as an indicator, may prove useful in signaling numerous forms of inflammatory reactions. The demonstration of anaphylatoxins in clinical samples is being recognized as a valuable diagnostic tool in monitoring the onset of immune disease.

  17. Analysis of Deregulated microRNAs and Their Target Genes in Gastric Cancer.

    Directory of Open Access Journals (Sweden)

    Simonas Juzėnas

    Full Text Available MicroRNAs (miRNAs are widely studied non-coding RNAs that modulate gene expression. MiRNAs are deregulated in different tumors including gastric cancer (GC and have potential diagnostic and prognostic implications. The aim of our study was to determine miRNA profile in GC tissues, followed by evaluation of deregulated miRNAs in plasma of GC patients. Using available databases and bioinformatics methods we also aimed to evaluate potential target genes of confirmed differentially expressed miRNA and validate these findings in GC tissues.The study included 51 GC patients and 51 controls. Initially, we screened miRNA expression profile in 13 tissue samples of GC and 12 normal gastric tissues with TaqMan low density array (TLDA. In the second stage, differentially expressed miRNAs were validated in a replication cohort using qRT-PCR in tissue and plasma samples. Subsequently, we analyzed potential target genes of deregulated miRNAs using bioinformatics approach, determined their expression in GC tissues and performed correlation analysis with targeting miRNAs.Profiling with TLDA revealed 15 deregulated miRNAs in GC tissues compared to normal gastric mucosa. Replication analysis confirmed that miR-148a-3p, miR-204-5p, miR-223-3p and miR-375 were consistently deregulated in GC tissues. Analysis of GC patients' plasma samples showed significant down-regulation of miR-148a-3p, miR-375 and up-regulation of miR-223-3p compared to healthy subjects. Further, using bioinformatic tools we identified targets of replicated miRNAs and performed disease-associated gene enrichment analysis. Ultimately, we evaluated potential target gene BCL2 and DNMT3B expression by qRT-PCR in GC tissue, which correlated with targeting miRNA expression.Our study revealed miRNA profile in GC tissues and showed that miR-148a-3p, miR-223-3p and miR-375 are deregulated in GC plasma samples, but these circulating miRNAs showed relatively weak diagnostic performance as sole biomarkers

  18. Xeroderma pigmentosum complementation group G associated with Cockayne syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Vermeulen, W.; Jaspers, N.G.J.; Bootsma, D.; Hoeijmakers, J.H.J. (Erasmus Univ., Rotterdam (Belgium)); Jaeken, J. (Univ. Hospital Gasthuisberg, Leuven (Belgium))

    1993-07-01

    Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are two rare inherited disorders with a clinical and cellular hypersensitivity to the UV component of the sunlight spectrum. Although the two traits are generally considered as clinically and genetically distinct entities, on the biochemical level a defect in the nucleotide excision-repair (NER) pathway is involved in both. Classical CS patients are primarily deficient in the preferential repair of DNA damage in actively transcribed genes, whereas in most XP patients the genetic defect affects both [open quotes]preferential[close quotes] and [open quotes]overall[close quotes] NER modalities. Here the authors report a genetic study of two unrelated, severely affected patients with the clinical characteristics of CS but with a biochemical defect typical of XP. By complementation analysis, using somatic cell fusion and nuclear microinjection of cloned repair genes, they assign these two patients to XP complementation group G, which previously was not associated with CS. This observation extends the earlier identification of two patients with a rare combined XP/CS phenotype within XP complementation groups B and D, respectively. It indicates that some mutations in at least three of the seven genes known to be involved in XP also can result in a picture of partial or even full-blown CS. It is concluded that the syndromes XP and CS are biochemically closely related and may be part of a broader clinical disease spectrum. The authors suggest, as a possible molecular mechanism underlying this relation, that the XPGC repair gene has an additional vital function, as shown for some other NER genes. 33 refs., 5 tabs.

  19. Graphs whose complement and square are isomorphic

    DEFF Research Database (Denmark)

    Milanic, M.; Pedersen, Anders Sune; Pellicer, D.;

    2014-01-01

    We study square-complementary graphs, that is, graphs whose complement and square are isomorphic. We prove several necessary conditions for a graph to be square-complementary, describe ways of building new square-complementary graphs from existing ones, construct infinite families of square...

  20. Cross-Cultural Analysis on Complements

    Institute of Scientific and Technical Information of China (English)

    刘恒

    2014-01-01

    Nativized varieties of English must reflect native pragmatic norms and cultural conventions. Complements, as a polite social behavior, is analyzed from the perspective of Chinese English speaker and American English speaker to emphasize the im-portance of the cross-cultural differences in pragmatic uses.